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.

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 wild-type or 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 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 wild-type and mutation, respectively. In these models, fulvestrant or elacestrant upregulated the expression of several 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.