# FGFR Aberrations in Solid Tumors: Mechanistic Insights and Clinical Translation of Targeted Therapies

## TL;DR

This review explores how changes in FGFR proteins drive cancer growth and how targeted therapies can be used to treat these tumors, while also addressing challenges like drug resistance.

## Contribution

The paper provides a comprehensive synthesis of FGFR aberrations' mechanisms and clinical implications, offering insights into precision oncology strategies.

## Key findings

- FGFR alterations drive tumor progression through multiple signaling pathways and tumor microenvironment changes.
- Selective FGFR inhibitors like pemigatinib and erdafitinib show clinical benefits but face resistance due to secondary mutations and bypass pathways.
- Emerging therapies such as antibody–drug conjugates and nanotechnology-based systems may enhance treatment durability.

## Abstract

Cancer treatment is increasingly guided by tumor DNA alterations. Changes in fibroblast growth factor receptors, a family of four related proteins, occur across many solid tumors and drive growth, spread, and treatment response by activating multiple signaling pathways. This review examines how these receptor changes—amplifications, mutations, and fusions—differ in their mechanisms and distribution across cancer types, and how they reshape the tumor environment, blood supply, and immune landscape. We summarize the clinical benefits and limitations of approved targeted drugs, explain why resistance develops through secondary mutations or alternative signaling routes, and describe how blood-based tests may detect resistance early. We also discuss next-generation strategies including combination with immunotherapy or anti-vessel therapy, antibody–drug conjugates, and nanotechnology-based delivery systems. By integrating molecular, translational, and clinical evidence, this review aims to guide patient selection, treatment monitoring, and the design of durable precision therapies targeting these receptor abnormalities.

Aberrations in fibroblast growth factor receptors (FGFRs) constitute a key oncogenic mechanism across multiple solid tumors, influencing tumor initiation, therapeutic response, and clinical outcomes. This review synthesizes current knowledge on the molecular biology, signaling networks, and tumor-specific distribution of FGFR alterations, including amplifications, point mutations, and gene fusions. The mechanistic basis of FGFR-driven tumor progression is discussed, including activation of downstream signaling pathways, crosstalk with other receptor tyrosine kinases, and regulation of the tumor microenvironment, angiogenesis, and immune escape. Recent development of selective FGFR inhibitors—such as pemigatinib, erdafitinib, and futibatinib—has translated mechanistic insights into measurable clinical benefits in genomically defined patient populations. However, acquired resistance remains a major challenge, driven by secondary mutations, activation of bypass pathways, and intratumoral heterogeneity. Integration of multi-omics profiling, liquid biopsy monitoring, and biomarker-guided patient selection is essential to optimize therapeutic efficacy and overcome resistance. This review also highlights emerging therapeutic modalities, such as antibody–drug conjugates and nanotechnology-based delivery systems, which may improve target specificity and prolong therapeutic durability. By integrating molecular, translational, and clinical evidence, this review aims to establish a comprehensive framework for precision oncology strategies targeting FGFR-driven malignancies.