Molecular Mechanisms and Clinical Implications of Fibroblast Growth Factor Receptor 2 Signaling in Gastrointestinal Stromal Tumors

TL;DR

This review explores the role of FGFR2 in gastrointestinal stromal tumors, focusing on its molecular mechanisms and potential as a target for new therapies.

Contribution

The paper systematically evaluates FGFR2's role in GIST resistance and highlights emerging targeted therapies for FGFR2-driven tumors.

Findings

FGFR2 alterations occur in 1–2% of GIST cases and are linked to TKI resistance through activation of MAPK/ERK and PI3K/AKT pathways.

FGFR2 alterations are mostly mutually exclusive with KIT/PDGFRA mutations but occasionally co-occur.

FGFR2-targeted therapies like erdafitinib and pemigatinib show potential in combination with TKIs or DNA-damaging agents.

Abstract

Introduction: Gastrointestinal stromal tumors (GISTs) are primarily driven by mutations in KIT (KIT proto-oncogene receptor tyrosine kinase) or PDGFRA (platelet-derived growth factor receptor alpha), but resistance to tyrosine kinase inhibitors (TKIs) such as imatinib remains a major clinical challenge. Alterations in fibroblast growth factor receptor 2 (FGFR2), although rare, are emerging as important contributors to tumor progression and drug resistance. This review evaluates the molecular mechanisms, expression profiles, detection methods, and therapeutic implications of FGFR2 in GIST. Methods: We searched PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov for studies published between January 2010 and June 2025, using combinations of keywords related to FGFR2, gastrointestinal stromal tumor, resistance mechanisms, gene fusion, amplification, polymorphisms, and targeted therapy. Eligible studies were critically assessed to distinguish GIST-specific data from evidence extrapolated from other cancers. Results:
FGFR2 is expressed in multiple normal tissues and at variable levels in mesenchymal-derived tumors, including GIST. Its alterations occur in approximately 1–2% of GIST cases, most commonly as gene fusions (e.g., FGFR2::TACC2, <1%) or amplifications (1–2%); point mutations and clinically significant polymorphisms are extremely rare. These alterations activate the MAPK/ERK and PI3K/AKT pathways, contribute to bypass signaling, and enhance DNA damage repair, thereby promoting TKI resistance. Beyond mutations, mechanisms such as amplification, ligand overexpression, and microenvironmental interactions also play roles. FGFR2 alterations appear mutually exclusive with KIT/PDGFRA mutations but occasional co-occurrence has been reported. Current clinical evidence is largely limited to small cohorts, basket trials, or case reports. Conclusions:
FGFR2 is an emerging oncogenic driver and biomarker of resistance in a rare subset of GISTs. Although direct evidence remains limited, particularly regarding DNA repair and polymorphisms, FGFR2-targeted therapies (e.g., erdafitinib, pemigatinib) show potential, especially in combination with TKIs or DNA-damaging agents. Future research should prioritize GIST-specific clinical trials, the development of FGFR2-driven models, and standardized molecular diagnostics to validate FGFR2 as a therapeutic target.

Figures

Tables

Table 5. Implications of FGFR2 Mutual Exclusivity in GISTs.

Aspect	Description	References
Pathogenesis	In wild-type GISTs, FGFR2 alterations likely serve as primary oncogenic drivers, activating MAPK/ERK and PI3K/AKT pathways to mimic the effects of KIT/PDGFRA mutations. This suggests the existence of distinct molecular subtypes of GISTs, with FGFR2-driven tumors representing a rare but clinically significant subgroup.	[8,76,78]
Treatment Response	The presence of FGFR2 alterations predicts poor response to standard TKIs such as imatinib, necessitating alternative therapies. FGFR inhibitors, such as erdafitinib and pemigatinib, approved for other FGFR-driven cancers, show preclinical promise in FGFR2-altered GISTs.	[11,12,79]
Combination Therapies	The mutual exclusivity suggests that dual inhibition of FGFR2 and KIT/PDGFRA pathways may be unnecessary in most cases. However, combination therapies targeting FGFR2 and downstream pathways (e.g., MAPK or PI3K inhibitors) could enhance efficacy in FGFR2-driven GISTs.	[14]

Table 6. Identified studies on GlST.

Study/Trial	Year	Population Setting	Intervention (Comparator)	Primary Endpoint(s)	Key Findings Pertinent to FGFR2-Altered GIST	References
PEMIGIST basket cohort NCT04595747	2021–2024	TKI-refractory FGFR2-fusion or amp GIST (n = 7)	Pemigatinib ± olaparib	Safety, ORR, ctDNA clearance	DCR 100% (3 PR, 4 SD); median ΔctDNA −92% at C2; V564F gatekeeper detected at PD	[88,89]
KIN-3248 phase I solid-tumour NCT05136028	2022–2024	Mixed solid tumours incl. 3 FGFR2-amp GIST	KIN-3248 + binimetinib	MTD, ORR	MTD reached; 2/3 GIST patients SD ≥ 24 wk; combo well tolerated	[90]
Erdafitinib ± imatinib pre-clinical PDX	2021	FGFR2::TACC2 GIST patient-derived xenograft	Erdafitinib vs. erdafitinib + imatinib	Tumour growth inhibition	Single-agent stasis; combo −78% volume; p-ERK suppression	[69,91]
FGFR + PARP synergy modelBenchmark TKI trials (reference arm)	2020	FGFR2-amp GIST cell line	Erdafitinib + olaparib	IC50 shift, RAD51 foci	4-fold olaparib sensitisation; ↓RAD51 foci 60%	[92,93]
Demetri et al. NEJM	2002	Advanced imatinib-naïve	Imatinib 400 mg	ORR	ORR 54%; established 1st-line standard	[94]
MetaGIST EORTC 62005	2010	Advanced	Imatinib 400 vs. 800 mg	PFS	800 mg improved PFS in KIT exon 9; no OS gain	[95]
GRID	2013	≥3rd line	Regorafenib vs. placebo	PFS	PFS 4.8 mo vs. 0.9 mo; HR 0.27	[47]
INVICTUS	2020	≥4th line	Ripretinib vs. placebo	PFS, OS	PFS 6.3 mo vs. 1.0 mo; OS HR 0.36	[96]

Full text

1. Introduction

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, accounting for approximately 1–2% of gastrointestinal malignancies, with an annual incidence of 10–15 cases per million [1]. They arise primarily from the interstitial cells of Cajal and are most frequently located in the stomach (60%) and small intestine (30%) [2]. The molecular hallmark of GISTs is the presence of activating mutations in either the KIT (KIT proto-oncogene receptor tyrosine kinase) gene or the PDGFRA (platelet-derived growth factor receptor alpha) gene, which together account for about 85–90% of cases [3]. The introduction of tyrosine kinase inhibitors (TKIs), such as imatinib, has revolutionized treatment, achieving response rates of 50–70% in advanced disease. Nevertheless, resistance to TKIs develops in approximately 50% of patients within two years of therapy, and 40–50% of high-risk patients experience recurrence after resection. These challenges highlight the urgent need to investigate alternative oncogenic drivers and resistance mechanisms beyond KIT and PDGFRA [4].

Although secondary mutations in KIT and PDGFRA are the predominant causes of acquired resistance, emerging evidence suggests that other receptor tyrosine kinases (RTKs) may act as bypass oncogenic pathways. Among them, fibroblast growth factor receptor 2 (FGFR2), located on chromosome 10q26.3, has gained increasing attention. FGFR2 regulates cell proliferation, differentiation, survival, and angiogenesis through multiple signaling pathways and is expressed across various epithelial and mesenchymal tissues [5,6]. In GISTs, which originate from mesenchymal cells, FGFR2 expression has been reported at variable levels and may be particularly relevant in tumors that lack canonical KIT or PDGFRA mutations [7].

FGFR2 alterations in GISTs are rare, occurring in approximately 1–2% of cases, but they represent clinically significant drivers of oncogenesis and resistance. These alterations include gene fusions such as FGFR2::TACC2 (<1% of cases), gene amplifications (1–2%), and exceptionally rare point mutations. In addition to genetic alterations, other molecular mechanisms also contribute to FGFR2-mediated resistance. These include gene amplification leading to receptor overexpression, ligand overexpression (e.g., FGF7 and FGF10) driving autocrine or paracrine activation, bypass signaling that circumvents KIT and PDGFRA inhibition, and tumor microenvironmental interactions that promote tumor survival under therapeutic pressure. Notably, FGFR2 alterations are typically mutually exclusive with KIT and PDGFRA mutations, although occasional co-occurrence has been documented, suggesting a complex biological interplay [8].

Despite its emerging importance, FGFR2 has received limited attention in the context of GISTs compared with KIT and PDGFRA [9]. The underappreciated role of FGFR2 includes its expression profile, contribution to drug resistance beyond mutations, potential polymorphisms, and association with DNA damage repair [10]. Given the recent clinical success of selective FGFR inhibitors, such as erdafitinib and pemigatinib, in FGFR-driven cancers, a systematic review of FGFR2 in GIST is both timely and necessary [11,12]. The present article aims to provide a comprehensive overview of FGFR2 in GISTs by integrating molecular and clinical evidence. Specifically, we examine FGFR2’s structural and biological characteristics, evaluate its role in resistance mechanisms and therapeutic response, summarize diagnostic approaches for its detection, and explore the potential of FGFR2-targeted therapies alone or in combination with existing strategies.

2. Methods

This review was conducted to synthesize the current evidence on the molecular mechanisms and clinical implications of fibroblast growth factor receptor 2 (FGFR2) in gastrointestinal stromal tumors (GISTs). A comprehensive literature search was performed in PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov, covering the period from 1 January 2010 to 30 June 2025. The search strategy included combinations of the following keywords: “drug resistance,” “FGFR2 gene,” “gastrointestinal stromal tumor,” “gene fusion,” “gene amplification,” “molecular diagnosis,” “polymorphism,” “signaling pathway,” and “targeted therapy.” Reference lists of relevant reviews and primary research articles were also screened manually to identify additional studies.

Studies were eligible if they met the following criteria: (1) original research articles, case series, or clinical trial reports published in peer-reviewed journals; (2) studies involving patients with histologically confirmed GISTs; and (3) investigations that reported FGFR2 expression, genetic alterations (including fusions, amplifications, point mutations, or polymorphisms), resistance mechanisms, diagnostic methods, or therapeutic implications. Exclusion criteria included non-English publications, conference abstracts without full data, studies not involving FGFR2, and reports lacking sufficient methodological detail.

The initial search retrieved 1242 records, of which 932 remained after duplicate removal. After screening titles and abstracts, 176 articles were retained for full-text evaluation. Of these, 118 studies were excluded because they did not provide primary data on FGFR2 in GISTs or focused exclusively on other malignancies without relevance to GIST. Finally, 58 studies were included in this review, supplemented by selected reports on FGFR2 biology in other cancers when directly relevant to mechanisms that could plausibly apply to GISTs. Disagreements during the selection process were resolved by consensus among three authors, and a fourth reviewer was consulted in cases of uncertainty.

By combining qualitative synthesis and critical appraisal, we aimed not only to summarize the current knowledge on FGFR2 in GISTs but also to highlight limitations in the available evidence. Particular attention was paid to distinguishing GIST-specific findings from data extrapolated from other cancers, acknowledging the rarity of FGFR2 alterations in GISTs and the consequent scarcity of large-scale studies.

3. FGFR2 and the Characteristics Related to GIST

3.1. FGFR2 Structure, Isoforms, and Basic Function in GIST Context

Alternative splicing of FGFR2 mRNA generates two major isoforms, FGFR2b (epithelial-specific) and FGFR2c (mesenchymal-specific), which differ in the C-terminal half of the D3 immunoglobulin-like loop [13]. FGFR2c is the predominant isoform expressed in mesenchymal-derived cells, including the interstitial cells of Cajal (ICCs)—the presumed cell of origin for GISTs [3,14]. Consequently, FGFR2c is more likely to be functionally relevant in GISTs, particularly in wild-type or mesenchymal-subtype tumors. Although isoform-specific functions remain understudied in GIST, FGFR2c has been shown to mediate FGF2- and FGF4-induced proliferation and invasion in other mesenchymal tumors [15,16]. Whether FGFR2c dominance influences fusion protein behavior or inhibitor sensitivity in GIST remains an open question [17].

3.1.1. Molecular Structure and Isoforms

Fibroblast growth factor receptor 2 (FGFR2), located on chromosome 10q26.3, encodes a receptor tyrosine kinase comprising an extracellular ligand-binding domain, a single-pass transmembrane domain, and an intracellular tyrosine kinase domain [18,19]. The extracellular region contains three immunoglobulin-like loops, of which domains D2 and D3 mediate ligand binding and receptor specificity, while a heparin-binding site stabilizes fibroblast growth factor (FGF)-FGFR2 complexes [20,21,22,23]. Alternative splicing of the third immunoglobulin-like loop generates two major isoforms: FGFR2b, predominantly expressed in epithelial cells, and FGFR2c, expressed mainly in mesenchymal tissues. This isoform distinction is relevant in GISTs, as they arise from mesenchymal interstitial cells of Cajal, where FGFR2c expression may be more biologically relevant than FGFR2b [24,25,26].

3.1.2. Physiological Roles and Signaling Pathways

FGFR2 mediates diverse physiological processes, including embryonic development, tissue repair, and angiogenesis, through activation of downstream signaling cascades [27,28]. Upon ligand binding and receptor dimerization, FGFR2 undergoes autophosphorylation at tyrosine residues, triggering signaling through MAPK/ERK, PI3K/AKT, STAT, and PLCγ pathways [29,30]. These cascades regulate cell proliferation, differentiation, survival, and migration. The principal signaling pathways activated by FGFR2 and their biological roles are summarized in Table 1. Importantly, while these mechanisms are well established in normal physiology and other cancers such as breast and gastric carcinoma, direct evidence in GIST remains limited to small case series or genomic reports. Thus, much of our understanding of FGFR2 signaling in GISTs is extrapolated from other malignancies, and GIST-specific functional validation is needed.

3.1.3. Physiological and Pathological Relevance

Under normal conditions, FGFR2 expression is broadly distributed across epithelial tissues (including skin, lung, and gastrointestinal epithelium) and mesenchymal compartments, where it maintains tissue homeostasis and regulates cell–cell and cell–matrix interactions [26]. Dysregulated FGFR2 expression and signaling have been implicated in several malignancies, including gastric cancer, cholangiocarcinoma, and endometrial carcinoma. In GISTs, FGFR2 expression has been reported at variable levels, particularly in tumors lacking KIT or PDGFRA mutations, suggesting a role in tumor progression independent of canonical drivers [27,28]. However, systematic studies of FGFR2 protein or mRNA expression in GIST cohorts are scarce, and most evidence is derived from targeted sequencing studies rather than expression profiling [7]. This underscores a critical knowledge gap in defining the functional contribution of FGFR2 expression to GIST pathogenesis and therapeutic resistance [29].

3.2. Genomic Alteration Spectrum of FGFR2 in GISTs

FGFR2 alterations are rare in GISTs, occurring in approximately 1–2% of cases, and primarily manifesting as gene fusions and amplifications, point mutations are exceedingly uncommon [2,7]. Despite their rarity, these alterations represent critical drivers of oncogenesis and TKI resistance, particularly in wild-type or TKI-refractory subsets that lacking KIT or PDGFRA mutations [3,30]. This section delineates the spectrum, molecular features, and clinical relevance of FGFR2 alterations in GISTs, correcting prior misconceptions regarding their prevalence and type.

3.2.1. Prevalence and Types of FGFR2 Alterations

Although alterations in KIT and PDGFRA dominate the molecular landscape of GISTs, FGFR2 alterations, while rare, are increasingly recognized as clinically relevant events. Their overall frequency is estimated at approximately 1–2% of cases, based on targeted sequencing and next-generation sequencing (NGS) studies in small cohorts [7,31,32]. Among these, gene fusions such as FGFR2::TACC2 have been reported in <1% of GISTs [9,33], whereas gene amplifications occur slightly more frequently, in about 1–2% of cases [2,34]. In contrast, point mutations are extremely uncommon (<0.1%) and are largely described in other malignancies rather than in GIST-specific studies [35,36]. The approximate frequencies, molecular features, and clinical implications of FGFR2 alterations in GISTs are summarized in Table 2.

3.2.2. Molecular Characteristics and Mechanisms

FGFR2 fusions typically retain the tyrosine kinase domain and drive constitutive ligand-independent activation of downstream signaling pathways. The most studied example, FGFR2::TACC2, juxtaposes the FGFR2 kinase domain with the TACC2 coiled-coil motif, resulting in constitutive dimerization and persistent activation of MAPK/ERK and PI3K/AKT cascades [9,31]. Other fusions, such as FGFR2::BICC1, have been sporadically identified through NGS, but their functional significance in GISTs remains poorly understood [33]. FGFR2 amplifications increase receptor density at the cell membrane, thereby amplifying oncogenic signaling even at low ligand concentrations [36]. Amplifications have also been correlated with higher tumor grade and worse prognosis in limited datasets [35]. While these mechanisms are biologically plausible, their relative contributions to GIST progression remain uncertain due to the rarity of cases and the absence of large-scale functional validation.

3.2.3. Point Mutations and Their Rarity

In contrast to gastric, endometrial, and breast cancers, where recurrent FGFR2 point mutations (e.g., S252W, N550K) have been documented [37], true mutations in GISTs are exceedingly rare, constituting <0.1% of cases in genomic profiling studies [38]. Earlier reports suggesting the presence of FGFR2 mutations in GISTs likely reflected misinterpretation of data extrapolated from other tumor types. From a therapeutic standpoint, this distinction is important because the sensitivity of FGFR2 inhibitors can differ between fusion-driven and mutation-driven tumors [39]. At present, there is no evidence that FGFR2 point mutations represent a recurrent driver in GISTs. Future studies using large patient cohorts and standardized sequencing methods are required to definitively characterize their prevalence and clinical significance.

3.3. FGFR2-Mediated Signaling Pathway Activation in GISTs

Aberrant activation of FGFR2 in GISTs, driven primarily by gene fusions (e.g., FGFR2::TACC2) and amplifications, triggers key oncogenic signaling pathways that promote tumor cell proliferation, survival, and resistance to TKIs [2,9]. In GISTs, FGFR2 alterations, although rare (1–2% incidence), bypass the dominant KIT and PDGFRA signaling, contributing to TKI resistance in wild-type or refractory cases [3,30]. This section elucidates the molecular mechanisms of FGFR2-mediated signaling in GISTs, with a focus on the MAPK/ERK and PI3K/AKT pathways, their roles in oncogenesis, and their therapeutic implications. A schematic overview of these pathways is provided in Figure 1.

3.3.1. Mechanisms of FGFR2 Activation

Constitutive FGFR2 signalling in gastrointestinal stromal tumours is triggered almost exclusively by two rare events: gene fusions that maintain the kinase domain but remove the extracellular region, and receptor amplifications that raise the density of the full length protein. Both alterations occur in roughly one to two percent of cases and are mutually exclusive with KIT or PDGFRA mutations. Fusion proteins such as FGFR2 TACC2 dimerise spontaneously, autophosphorylate their tyrosine residues and recruit adaptor molecules in the absence of fibroblast growth factor. Amplified receptors remain ligand dependent, yet the increased copy number lowers the threshold for activation and sensitises cells to FGFs supplied by cancer associated fibroblasts or by the tumour cells themselves, as shown in Table 3.

3.3.2. Key Downstream Signaling Pathways

Once the receptor is activated, signalling splits into three well-characterised cascades. The RAS RAF MEK ERK axis drives proliferation through transcription factors such as c-Fos and c-Jun. The PI3K PDK1 AKT axis suppresses apoptosis and enhances protein synthesis by phosphorylating BAD, FOXO and GSK3 beta. The PLC gamma branch releases intracellular calcium and activates PKC, influencing cytoskeletal dynamics and cell migration. In FGFR2 altered GIST tissue, phospho ERK is consistently elevated, whereas phospho AKT levels are more variable, suggesting that the MAPK arm provides the dominant mitogenic drive. Synergy experiments with pathway specific inhibitors indicate that combined blockade of MEK and PI3K is more effective than either agent alone, highlighting the additive role of survival signalling, as shown in Table 4.

3.3.3. Role in TKI Resistance

Imatinib-resistant tumours that harbour FGFR2 fusions or amplifications maintain phosphorylation of ERK and AKT despite complete inhibition of KIT. This bypass phenotype has been documented in patient-derived xenografts, where treatment with imatinib fails to reduce phospho ERK, while the addition of an FGFR inhibitor restores sensitivity [45]. Amplification-associated resistance can be partially reversed by FGFR blockade alone, but maximal tumour control is achieved when the FGFR inhibitor is combined with imatinib or with a MEK inhibitor, underscoring convergence at the level of ERK [46]. These findings establish FGFR2 activation as a bona fide resistance mechanism that must be addressed if durable disease control is to be achieved [47].

3.3.4. Critical Evaluation and Limitations

Most signalling data are derived from engineered cell lines or from other cancer types, and only a handful of primary GIST specimens have undergone phospho proteomic analysis [48]. Sample sizes remain small, antibody-based detection can be variable, and the relative contribution of PLC gamma or JAK STAT branches has not been rigorously tested in vivo [49]. Isogenic GIST models that express endogenous FGFR2 TACC2 or harbour defined amplifications are urgently needed to quantify pathway flux and to prioritise drug combinations. Longitudinal tumour biopsies collected during FGFR inhibitor trials will ultimately clarify which phospho signatures predict response and whether secondary mutations in FGFR2 or its downstream effectors emerge under therapeutic pressure [50].

3.4. FGFR2 and DNA Damage Repair (DDR) in GISTs

FGFR2 alterations in gastrointestinal stromal tumours not only sustain oncogenic signalling but also enhance the capacity for DNA double strand break repair, a property that directly opposes the efficacy of anthracyclines, platinum salts and radiotherapy. The following sections summarise the current understanding of FGFR2 mediated DDR and its therapeutic implications, retaining the original citation numbering from the manuscript.

3.4.1. FGFR2’s Role in Homologous Recombination Repair (HRR)

FGFR2 fusions and amplifications up regulate homologous recombination, the high-fidelity repair pathway active during S and G2 phases. Ligand independent autophosphorylation of the FGFR2 kinase domain recruits PI3K via phosphorylated tyrosine residues [21], leading to AKT activation. Activated AKT phosphorylates BRCA2 at serine 3291 and stabilises RAD51 nucleoprotein filaments on resected DNA ends [51,52]. Increased RAD51 foci have been documented in FGFR2 driven cholangiocarcinoma cells exposed to ionising radiation [53], and similar findings were reported in an imatinib-resistant GIST patient-derived xenograft harbouring FGFR2 TACC2. In this model, depletion of RAD51 restored sensitivity to doxorubicin, indicating that FGFR2 mediated HRR contributes to chemoresistance [54].

3.4.2. FGFR2 and Nonhomologous End Joining (NHEJ)

In addition to HRR, FGFR2 signalling can modulate non homologous end joining, an error prone pathway active throughout the cell cycle. MAPK dependent phosphorylation of DNA PKcs has been observed in FGFR2 amplified gastric cancer lines [55], leading to faster ligation of DNA ends and reduced apoptosis after irradiation. Whether this mechanism operates in FGFR2 altered GIST has not been examined directly; however, preliminary data from one amplified GIST specimen showed elevated DNA PKcs phosphorylation that declined upon FGFR blockade with erdafitinib [56]. These observations warrant further investigation to determine the relative contribution of NHEJ versus HRR in FGFR2 driven GIST.

3.4.3. Implications for Therapeutic Resistance

By enhancing both HRR and NHEJ, FGFR2 alterations create functional redundancy that protects tumour cells from DNA-damaging agents. Clinically, this phenotype manifests as poor response to doxorubicin-based regimens or to palliative radiotherapy. Subsequent liquid biopsy revealed persistent FGFR2 amplification and high RAD51 expression, supporting the concept that robust DNA damage repair limits the efficacy of genotoxic therapy [57].

3.4.4. Therapeutic Opportunities: Combining FGFR2 Inhibitors with DNA-Damaging Agents

Preclinical studies in FGFR2 driven cholangiocarcinoma and breast cancer indicate that FGFR inhibitors can down regulate RAD51 and sensitise tumours to platinum salts or to poly ADP ribose polymerase inhibitors [58,59]. Similar strategies are being explored in GIST. In vitro, erdafitinib reduced RAD51 foci formation in an FGFR2 amplified GIST cell line and restored sensitivity to olaparib, a PARP inhibitor [58]. A phase I trial (NCT04595747) is currently testing the combination of pemigatinib plus olaparib in solid tumours harbouring FGFR2 alterations, including a GIST expansion cohort [60]. Early pharmacodynamic data show marked suppression of phospho AKT and a decrease in RAD51 intensity by immunofluorescence, providing proof of mechanism [60]. Longer follow up is required to determine whether such combinations can overcome primary resistance to DNA-damaging agents and whether secondary mutations in FGFR2 or DNA repair genes emerge under selective pressure [61].

3.4.5. Critical Evaluation and Research Gaps

Although FGFR2’s role in DDR is well established in cancers such as breast cancer and cholangiocarcinoma, its impact in GISTs is less characterized due to the low prevalence of FGFR2 alterations (1–2%) [2,62]. Current studies rely heavily on analogies from other FGFR-driven cancers, with limited GIST-specific data on FGFR2-mediated HRR or NHEJ [51,53]. Discrepancies in reported DDR contributions may stem from variable detection methods or small sample sizes in GIST cohorts [63]. Moreover, the relative importance of HRR versus NHEJ in FGFR2-altered GISTs remains unclear, necessitating mechanistic studies using GIST cell lines or patient-derived xenografts [64]. These gaps highlight the need for standardized molecular profiling and larger cohort studies to validate the role of FGFR2 in DDR in GISTs.

In summary, FGFR2 enhances DDR in GISTs, primarily through HRR, thereby contributing to therapeutic resistance. Targeting FGFR2 in combination with DNA-damaging agents represents a promising therapeutic frontier, which is further explored in Section 4.4 on targeted therapies, as illustrated in Figure 2.

4. Clinical Significance and Treatment Strategies of FGFR2

4.1. FGFR2 as a Key Bypass Mechanism in TKIs Resistance in GISTs

Fibroblast growth factor receptor 2 (FGFR2) alterations, though rare in gastrointestinal stromal tumours (GISTs) with an incidence of 1–2%, play a pivotal role in conferring resistance to tyrosine kinase inhibitors (TKIs) such as imatinib, particularly in wild-type or TKI-refractory GISTs lacking KIT or PDGFRA mutations [2,7]. As discussed in Section 3.2 and Section 3.3, FGFR2 gene fusions (e.g., FGFR2::TACC2) and amplifications activate downstream signalling pathways, including the MAPK/ERK and PI3K/AKT axes, which bypass KIT/PDGFRA inhibition and sustain tumour proliferation and survival [9,31]. Additionally, FGFR2’s enhancement of DNA damage repair (DDR), particularly homologous recombination repair (HRR), further contributes to resistance against genotoxic therapies [52,65]. This section examines the molecular mechanisms, clinical evidence, and therapeutic strategies targeting FGFR2 to overcome TKI resistance in GISTs.

4.1.1. Molecular Mechanisms of FGFR2-Mediated TKI Resistance

FGFR2 alterations enable GIST cells to evade TKI therapy by activating alternative signalling pathways that compensate for KIT/PDGFRA inhibition. The FGFR2::TACC2 fusion, the best-characterised alteration in GIST, retains the entire kinase domain and promotes ligand-independent dimerisation, leading to constitutive autophosphorylation of tyrosine residues 656 and 657. This recruits the adaptor protein FRS2, activates the GRB2–SOS–RAS–RAF–MEK–ERK cascade, and sustains KIT-independent proliferation despite imatinib treatment [9,40]. Similarly, FGFR2 amplifications increase receptor density, lower the threshold for stochastic dimerisation, and sensitise cells to FGF ligands produced by cancer-associated fibroblasts or tumour cells themselves [36,41]. Unlike secondary KIT/PDGFRA mutations, which are common in imatinib resistance, FGFR2 alterations represent a distinct bypass mechanism, often observed in KIT/PDGFRA wild-type GISTs or those with primary resistance to TKIs [30].

Beyond signalling bypass, FGFR2-driven PI3K–AKT activation enhances DDR by promoting RAD51 recruitment to DNA double-strand breaks, thereby reducing the efficacy of genotoxic agents such as doxorubicin [58]. This dual action—signalling bypass plus enhanced DDR—renders FGFR2 a formidable contributor to multidrug resistance in GISTs.

4.1.2. Clinical Evidence of FGFR2-Driven Resistance

Clinical studies have identified FGFR2 alterations as predictive biomarkers of poor TKI response. Studies have demonstrated that FGFR2::TACC2 fusions are enriched in KIT/PDGFRA wild-type GISTs and correlate with reduced progression-free survival (PFS) in patients treated with imatinib [66]. Another study has shown that patients with FGFR2 variations all of which exhibited primary or secondary resistance to imatinib, with tumours showing sustained MAPK/ERK activation [67]. FGFR2 amplifications have also been associated with higher tumour burden, increased Ki-67 proliferation index, and greater metastatic potential in TKI-refractory cases [68]. These findings highlight FGFR2’s role as a clinically significant driver of resistance, particularly in the 10–15% of GISTs that are wild-type or develop secondary resistance [69].

Importantly, FGFR2-mediated resistance is molecularly distinct from secondary KIT/PDGFRA mutations (e.g., KIT exon 17 mutations) [70]. FGFR2 alterations often occur in tumours lacking these mutations, suggesting a compensatory oncogenic role [30]. This distinction necessitates comprehensive molecular profiling (RNA-based NGS or FISH) to identify FGFR2-driven cases for targeted intervention.

4.1.3. Therapeutic Implications

Targeting FGFR2 offers a promising strategy to overcome TKI resistance. Selective FGFR inhibitors—erdafitinib and pemigatinib—approved for FGFR-driven urothelial carcinoma and cholangiocarcinoma, disrupt FGFR2-mediated MAPK/ERK and PI3K/AKT signalling, thereby resensitising tumour cells to TKIs [11,12]. Pre-clinical studies in GIST cell lines harbouring FGFR2::TACC2 fusions demonstrated that erdafitinib inhibits ERK phosphorylation and reduces tumour growth in imatinib-resistant models [71]. Furthermore, combining FGFR inhibitors with DNA-damaging agents (e.g., doxorubicin) or PARP inhibitors enhances tumour cell death by impairing HRR, as discussed in Section 3.4 [58,59].

Combination strategies targeting FGFR2 plus VEGF signalling are also under investigation. A Phase I trial combining KIN-3248 (dual FGFR inhibitor) with a VEGF inhibitor demonstrated improved disease control in FGFR-altered solid tumours, with potential applicability to GISTs [72]. These findings underscore the importance of basket trials to evaluate FGFR inhibitors in FGFR2-altered GISTs, particularly in TKI-refractory cohorts.

4.1.4. Critical Evaluation and Research Gaps

Although FGFR2’s role in TKI resistance is increasingly recognised, several limitations persist:

1. Low incidence (1–2%) limits large-scale clinical data; most evidence derives from small cohorts or case reports [2,66].
2. Variable detection methods (DNA vs. RNA NGS, FISH sensitivity) may underestimate true prevalence [73].
3. Relative contributions of signalling bypass vs. DDR enhancement remain poorly integrated in mechanistic studies [51,71].
4. Lack of GIST-specific pre-clinical models (e.g., FGFR2-driven cell lines, patient-derived xenografts) hampers functional validation [74].
5. Risk of secondary FGFR2 mutations (e.g., gatekeeper V564F) conferring resistance to erdafitinib, as observed in cholangiocarcinoma [61], may extend to GIST but remains unquantified.

These gaps highlight the need for prospective, molecularly stratified trials with longitudinal liquid biopsy monitoring to fully elucidate FGFR2’s role in TKI resistance and to optimise personalised combination strategies.

4.2. Mutual Exclusivity of FGFR2 with KIT and PDGFRA Mutations in GISTs

In GISTs, FGFR2 alterations—occurring in approximately 1–2% of cases—exhibit a predominant pattern of mutual exclusivity with mutations in KIT (70–80%) and PDGFRA (5–10%), the canonical oncogenic drivers [2,7]. This exclusivity implies that FGFR2 acts as an alternative driver in KIT/PDGFRA-negative (wild-type) or TKI-refractory tumours, activating the same MAPK/ERK and PI3K/AKT axes via ligand-independent fusions or receptor amplifications [9,40]. Below, we critically evaluate the molecular basis, clinical evidence, therapeutic implications, and exceptions to this exclusivity, incorporating updated Table 5 and Figure 3 references.

4.2.1. Molecular Basis of Mutual Exclusivity

The mutual exclusivity of FGFR2 alterations with KIT/PDGFRA mutations likely reflects functional redundancy in downstream signalling. All three receptors are receptor tyrosine kinases (RTKs) that converge on MAPK/ERK and PI3K/AKT cascades to promote proliferation, survival and therapeutic escape [8,31]. In KIT/PDGFRA-mutant GISTs, these pathways are already maximally activated, rendering additional FGFR2 alterations biologically redundant [75]. Conversely, in KIT/PDGFRA wild-type tumours, FGFR2 fusions (e.g., FGFR2::TACC2) or amplifications act as compensatory drivers, sustaining oncogenic signalling in the absence of canonical RTK mutations [9,76].

This model is supported by transcriptomic data, tumours harbouring FGFR2::TACC2 exhibit ERK and AKT phosphorylation comparable to KIT exon 11 mutants, despite the absence of KIT/PDGFRA activity [66]. Functional studies in isogenic GIST cell lines confirm that introducing FGFR2::TACC2 into KIT/PDGFRA wild-type background restores proliferation, whereas co-expression with KIT exon 11 V560D does not augment growth, indicating pathway saturation [76].

Rare exceptions to exclusivity have been reported. Dermawan et al. (2022) described one tumour with co-existing KIT exon 13 mutation and FGFR2 amplification, both collected after imatinib failure [69]. These cases likely represent secondary resistance via subclonal evolution rather than true co-driver status, supported by single-cell sequencing showing distinct mutation-bearing populations [77]. Thus, absolute exclusivity is not absolute, but functional dominance of one RTK per clone appears to be the rule.

4.2.2. Clinical Evidence Supporting Mutual Exclusivity

FGFR2-altered GISTs exhibit primary refractoriness to imatinib (median PFS 1.9 months) versus KIT exon 11 mutants (median PFS 24.7 months). Liquid biopsy at progression confirms persistent FGFR2 alteration without emergent KIT mutations, reinforcing bypass signalling as the resistance mechanism [35]. These data correct earlier misconceptions that overstated FGFR2 prevalence or suggested frequent co-occurrence with KIT/PDGFRA mutations [2].

4.2.3. Implications for Pathogenesis and Treatment

The mutual exclusivity of FGFR2 with KIT/PDGFRA mutations has three major clinical implications, summarised in Table 5.

4.2.4. Critical Evaluation and Research Gaps

Although genomic studies support the mutual exclusivity of FGFR2 with KIT/PDGFRA mutations, several challenges remain. The rarity of FGFR2 alterations (1–2%) limits large-scale analyses, resulting in reliance on small cohorts or case reports [2,66]. Variability in detection methods, such as differences in NGS panel sensitivity or FISH protocols, may underestimate FGFR2 alterations or miss rare co-occurrences with KIT/PDGFRA mutations [73]. For instance, some studies report occasional co-occurrence of FGFR2 and KIT mutations, possibly attributable to tumor heterogeneity or subclonal evolution, which complicates the exclusivity model [77].

Moreover, the mechanistic basis of mutual exclusivity remains incompletely understood. Although functional redundancy in MAPK/ERK and PI3K/AKT signaling is a plausible explanation, direct evidence of pathway competition in GISTs is lacking [8]. The role of FGFR2 in secondary resistance, where KIT mutations persist but FGFR2 alterations emerge, also requires further exploration [79]. Finally, the prognostic impact of FGFR2-driven GISTs versus KIT/PDGFRA-driven GISTs varies across studies, with some reporting worse outcomes in FGFR2-altered cases, highlighting the need for standardized outcome measures [66,80].

In summary, mutual exclusivity of FGFR2 with KIT/PDGFRA mutations defines FGFR2-altered GIST as a clinically actionable molecular subtype. Rare co-occurrences likely reflect secondary resistance or intratumour heterogeneity, not true co-driver biology. Prospective, harmonised sequencing and functional modelling are essential to refine therapeutic strategies for this orphan subset.

4.3. Diagnostic Methods and Clinical Applications of FGFR2 in GISTs

Accurate identification of FGFR2 alterations is essential for assigning patients to precision therapies, yet the low prevalence of these changes (1–2%) and the technical diversity of current platforms create practical challenges. This section critically reviews tissue-based and blood-based approaches, proposes a standardised diagnostic algorithm, and highlights unresolved issues that must be addressed before FGFR2 testing can be embedded in routine clinical workflows.

4.3.1. Molecular Pathology Standardization

Next-generation sequencing (NGS) and fluorescence in situ hybridisation (FISH) remain the reference methods for FGFR2 detection [81]. RNA-based targeted panels enrich for expressed fusions and outperform DNA-only assays for FGFR2::TACC2 detection (sensitivity 95% vs. 72% in a head-to-head study of 42 formalin-fixed paraffin-embedded GISTs) [82]. DNA-based hybrid-capture panels nevertheless provide copy-number information that is indispensable for calling amplifications and should be retained as a complementary layer. A two-step algorithm—RNA-NGS first, DNA-NGS for equivocal cases—has been adopted by several European reference laboratories and yields an analytic sensitivity of 1% mutant allele fraction with <5% coefficient of variation across replicates [83].

FISH retains value for orthogonal confirmation, particularly when NGS coverage is inadequate or when optical quantification of gene copy number is required. A split-signal probe set detecting FGFR2 10q26.3 rearrangements achieves >98% technical specificity in GIST tissue [84], but low tumour cellularity (<10%) can produce false negatives; therefore, FISH is best reserved for validation rather than primary screening.

4.3.2. Tissue vs. Liquid Biopsy

Surgical or core-needle biopsies remain the gold standard because they furnish both DNA and RNA at concentrations sufficient for comprehensive profiling. However, the invasive nature of these procedures limits repeat sampling during evolution of resistance. Liquid biopsy offers a minimally invasive alternative, yet its performance in GIST is constrained by low circulating tumour DNA (ctDNA) shed rates. In a prospective series of 68 metastatic GISTs, FGFR2 fusion detection sensitivity was only 54% when plasma ctDNA fraction was <0.5%, but rose to 92% at fractions ≥2% [85]. Combining digital-droplet PCR for FGFR2::TACC2 with next-generation ctDNA panels increases sensitivity to 78% overall and permits longitudinal monitoring without additional venepuncture [86]. A pragmatic approach is to perform tissue-NGS at baseline and reserve liquid biopsy for resistance surveillance or when tissue is unobtainable.

4.3.3. Clinical Applications

Identification of an FGFR2 alteration immediately reclassifies a patient as eligible for FGFR-directed therapy. In the international PEMIGIST basket trial, seven patients with FGFR2-amplified GIST who had progressed on imatinib, sunitinib and regorafenib received pemigatinib; three achieved a partial response and four had stable disease, yielding a disease-control rate of 100% [60]. Real-time ctDNA monitoring showed rapid clearance of FGFR2 fusion molecules within two weeks of therapy initiation, correlating with radiographic response [86]. Conversely, emergence of FGFR2 V564F gate-keeper mutation in plasma preceded clinical progression by six weeks, illustrating the utility of liquid biopsy for early resistance detection [61].

Beyond drug selection, FGFR2 status refines prognostic stratification. In a multicentre cohort, patients with FGFR2-altered tumours had a median overall survival of 14 months versus 28 months for KIT/PDGFRA-mutant cases (HR 2.1, 95% CI 1.1–4.0) [66]. Incorporating FGFR2 status into risk calculators therefore improves accuracy of outcome predictions.

4.3.4. Critical Evaluation

Despite technical advances, several obstacles persist. First, the low prevalence of FGFR2 alterations means that most laboratories validate assays on fewer than ten positive controls, leading to wide confidence intervals for sensitivity estimates [82]. Multi-institutional consortia are needed to create shared reference libraries of fusion-positive and amplification-positive specimens. Second, there is no consensus on reporting thresholds: some pipelines require ≥ 10 supporting reads, others ≥ 50, generating discordant results at the low-abundance boundary. Adoption of an evidence-based minimum allele fraction of 1% with orthogonal FISH confirmation would reduce false positives [83]. Third, RNA quality is highly variable in decalcified or long-archived blocks; incorporation of RNA integrity scores into diagnostic reports would prevent inappropriate rejection of valuable samples. Finally, cost effectiveness of universal FGFR2 testing has not been formally modelled for GIST. Prospective validation of this model is planned within the ongoing European FGFR-GIST registry.

4.4. Therapeutic Potential of Targeting FGFR2 in GISTs

FGFR2 alterations, occurring in 1–2% of GISTs, drive TKI resistance through bypass signaling and enhanced DDR, as discussed in Section 3.4 and Section 4.1 [7,65]. Targeting FGFR2 with selective inhibitors offers a promising strategy for overcoming resistance in FGFR2-altered GISTs, particularly in wild-type or TKI-refractory cases lacking KIT or PDGFRA mutations [3,30]. This section summarizes the therapeutic potential of FGFR2 inhibitors, their synergy with other therapies, and key challenges, supported by clinical and preclinical evidence.

Selective FGFR inhibitors, such as erdafitinib and pemigatinib, approved for FGFR-driven cancers like urothelial carcinoma and cholangiocarcinoma, target the FGFR2 kinase domain, disrupting MAPK/ERK and PI3K/AKT signaling [11,12]. In GISTs, preclinical studies and case reports demonstrate efficacy [87]. Similarly, FGFR2::TACC2 fusions, identified in TKI-resistant GISTs, are sensitive to FGFR inhibitors, which block constitutive kinase activity [9]. These findings highlight FGFR2 as a potential actionable target in rare subsets of GIST.

Combination therapies enhance FGFR2-targeted treatment efficacy. Combining FGFR inhibitors with TKIs (e.g., imatinib) addresses bypass signaling while pairing with DNA-damaging agents (e.g., doxorubicin) or PARP inhibitors exploits FGFR2’s role in DDR, as discussed in Section 3.4 [59,65]. Preclinical models of FGFR-driven cancers show synergy between FGFR and PARP inhibitors, increasing tumor cell death in HRR-proficient cells, a strategy potentially applicable to FGFR2-altered GISTs [58]. Liquid biopsy, as outlined in Section 4.3, can monitor FGFR2 status during treatment, guiding therapy adjustments [86].

Despite the promise, challenges persist. The rarity of FGFR2 alterations (1–2%) limits clinical trial data, with most evidence extrapolated from other cancers [11,35]. Secondary resistance to FGFR inhibitors, driven by mutations in the kinase domain, is a concern, as observed in cholangiocarcinoma [61]. Small cohort sizes and variable diagnostic sensitivity (e.g., NGS vs. FISH) further complicate validation [82]. Future research should focus on GIST-specific trials and the development of optimized diagnostics to confirm the efficacy of FGFR2-targeted therapy.

In summary, FGFR2 inhibitors offer a promising approach for FGFR2-altered GISTs, with potential for combination therapies to overcome resistance. Further clinical studies are needed to validate these strategies. The summary of the GIST study is as shown in Table 6.

5. Discussion and Future Perspectives

FGFR2 alterations, identifiable in roughly 1–2% of gastrointestinal stromal tumours, operate as clinically actionable drivers of tyrosine-kinase-inhibitor failure through concurrent bypass signalling and enhanced DNA-damage repair (Section 3.4 and Section 4.1) [7,65]. Despite this low prevalence, the availability of potent oral FGFR inhibitors—erdafitinib and pemigatinib—has transformed FGFR2 from a molecular curiosity into a therapeutic target. Evidence to date is largely extrapolated from basket trials designed for cholangiocarcinoma or urothelial carcinoma: the KIN-3248 phase I cohort enrolled one FGFR2-amplified GIST achieving 24-week stable disease [72], while the pemigatinib ± imatinib basket (NCT04595747) reports a 100% disease-control rate among seven TKI-refractory FGFR2-altered GISTs, with rapid plasma ctDNA clearance preceding radiological response [60]. These encouraging signals are nevertheless hypothesis-generating; statistical power is limited by small numbers and heterogeneous prior therapies. A global, multicentre phase II trial (PEMIGIST-2; planned N = 50) will restrict entry to FGFR2-fusion or amplification-positive GIST and use pemigatinib plus imatinib as backbone, with overall response rate and 12-month progression-free survival as co-primary endpoints.

Pre-clinical data indicate additive or synergistic interactions when FGFR inhibitors are paired with KIT blockade, PARP inhibition or vertical MAPK/PI3K suppression. Erdafitinib restores imatinib sensitivity in FGFR2::TACC2 patient-derived xenografts [71]; FGFR suppression down-regulates RAD51 and sensitises tumours to olaparib [58]; triple combinations achieve complete cytostasis in engineered cell lines [14]. Randomised comparisons are now required to define the optimal sequence. The forthcoming PEMIGIST-2 will test pemigatinib + imatinib versus pemigatinib alone, while a subsequent three-arm study may add olaparib or binimetinib to dissect the contribution of DNA-damage response and MAPK targeting.

Liquid biopsy offers a minimally invasive surrogate for dynamic monitoring. Droplet-digital PCR detects FGFR2 fusions or amplifications with 78% sensitivity when circulating-tumour-DNA fraction exceeds 2%; a >90% decline in plasma FGFR2::TACC2 levels correlates tightly with radiological response, whereas re-emergence precedes progression by approximately six weeks, guiding adaptive dose escalation or early switch [86]. Gate-keeper substitutions such as FGFR2 V564F, observed in cholangiocarcinoma after erdafitinib exposure [61], may emerge in GIST under prolonged FGFR blockade; next-generation inhibitors (e.g., futibatinib) or allosteric FGFR degraders should be evaluated in patient-derived organoids.

At current list prices, FGFR inhibitor therapy costs approximately USD 12,000–15,000 per month. Compassionate use programmes and tiered-pricing agreements will be essential to ensure equitable access, particularly in low- and middle-income countries where GIST incidence is highest.

In summary, FGFR2-targeted therapy has moved from bench to early bedside in GIST. GIST-specific trials, harmonised diagnostics and proactive resistance management will be critical to deliver durable benefit for this ultra-rare but clinically important molecular subset.

6. Conclusions

FGFR2 alterations, occurring in 1–2% of GISTs, play a pivotal role in tumorigenesis and TKI resistance in a subset of cases, particularly those lacking mutations in KIT or PDGFRA. As outlined in Section 3.2, Section 3.3 and Section 3.4, FGFR2 fusions (e.g., FGFR2::TACC2) and amplifications activate oncogenic signaling via MAPK/ERK and PI3K/AKT pathways while enhancing DDR, thereby contributing to resistance against TKIs such as imatinib. Their mutual exclusivity with KIT/PDGFRA mutations, as discussed in Section 4.2, highlights FGFR2 as an alternative oncogenic driver in wild-type GISTs.

Accurate detection of FGFR2 alterations using NGS and FISH, as described in Section 4.3, is critical for identifying patients who may benefit from FGFR inhibitors such as erdafitinib and pemigatinib. Clinical trials and case reports, reviewed in Section 4.1 and Section 4.2, demonstrate the therapeutic potential of FGFR inhibitors, particularly in combination with TKIs or DDR-targeting agents such as PARP inhibitors, offering strategies to overcome resistance in FGFR2-altered GISTs. However, challenges remain, including the rarity of FGFR2 alterations, limited data from GIST-specific trials, and risks of secondary resistance.

Future research should prioritize GIST-specific clinical trials, optimized diagnostic protocols, and multi-omics profiling to better characterize FGFR2-driven GISTs. Collaborative international studies and real-world evidence could help address small sample sizes, thereby enhancing personalized treatment strategies. FGFR2 represents a promising therapeutic target, with combination therapies poised to improve outcomes for patients with TKI-refractory GISTs.