# Effect of Tasurgratinib as an Orally Available FGFR1–3 Inhibitor on Resistance to a CDK4/6 Inhibitor and Endocrine Therapy in ER+/HER2− Breast Cancer Preclinical Models

## TL;DR

This study shows that tasurgratinib, an FGFR inhibitor, can help overcome resistance to CDK4/6 inhibitors and endocrine therapy in ER+/HER2− breast cancer.

## Contribution

The novel contribution is demonstrating tasurgratinib's potential to reverse drug resistance in ER+ breast cancer through FGFR inhibition.

## Key findings

- FGF signaling activation contributes to resistance to CDK4/6 inhibitors and endocrine therapy in ER+ breast cancer.
- Tasurgratinib, when combined with endocrine therapy, restores sensitivity and shows antitumor activity in resistant ER+ breast cancer models.
- Tasurgratinib inhibits FGF signaling, which is upregulated following CDK4/6 and endocrine therapy treatments.

## Abstract

Breast cancer is the most common cancer affecting women worldwide. Among breast cancer subtypes, estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)− breast cancer is the most prevalent category, with a prevalence of 70%. For this type of tumor, a combination of endocrine therapy and a CDK4/6 inhibitor serves as the standard of care in advanced or metastatic cases. Here, we investigated the role of fibroblast growth factor (FGF) signaling in resistance to CDK4/6 inhibitors and endocrine therapy, as well as the effects of tasurgratinib, an FGFR1–3 selective inhibitor, on drug resistance in preclinical ER+/HER2− breast cancer cell lines and patient-derived xenograft models. Our findings suggest that FGF signaling activation confers resistance to CDK4/6 inhibitors and endocrine therapy and that tasurgratinib shows antitumor activity in combination with endocrine therapy in endocrine therapy-resistant ER+ breast cancer.

Background: Fibroblast growth factor (FGF) signaling plays a crucial role in several cellular functions in cancer cells. Tasurgratinib, formerly known as E7090, is an orally available FGF receptor (FGFR)1–3 selective inhibitor. Here, we present the effects of tasurgratinib on the resistance to CDK4/6 inhibitors and endocrine therapy (ET) in a preclinical model. Methods: Estrogen receptor (ER)+ breast cancer (BC) patient-derived xenograft (PDX) models harboring ESR1 wild-type or ESR1 mutation were used as animal models. An in vitro cell proliferation assay of ER+ BC cell lines treated with fulvestrant or palbociclib + fulvestrant was conducted in the presence of FGF2 and FGF10, with or without tasurgratinib. Results: Among five ER+ BC PDX models, OD-BRE-0438 and OD-BRE-0704 showed higher sensitivities to tasurgratinib with prior palbociclib + fulvestrant than without it. In these models, palbociclib + fulvestrant treatment upregulated the expression of several FGF ligand mRNAs. In vitro, FGF2 and FGF10 decreased the sensitivity to both fulvestrant and palbociclib + fulvestrant, which was restored by co-treatment with tasurgratinib. Consistently, fulvestrant + tasurgratinib and elacestrant + tasurgratinib showed antitumor activity in ER+ BC PDX models harboring ESR1 wild-type and ESR1 mutation, respectively. In these models, fulvestrant or elacestrant upregulated the expression of several FGF ligand mRNAs. Conclusions: FGF signaling plays a role in resistance to CDK4/6 inhibitors and ET in ER+ BC. Tasurgratinib has the potential to exhibit significant antitumor activity in combination with ET against ER+ BC via FGF signaling inhibition. These findings indicate the therapeutic potential of tasurgratinib in treating ER+ BC.