Selective degradation of FGFR1/2 overcomes antiestrogen resistance in ER+ breast cancer with FGFR1/2 alterations.

FGFR1 amplification and FGFR1/2 activating mutations have been associated with antiestrogen resistance in estrogen receptor-positive (ER+) breast cancer. However, there are no approved FGFR1-targeted therapies for breast cancers harboring these alterations. In this study, we investigated the selective degradation of FGFR1/2 using the proteolysis-targeting chimera (PROTAC) DGY-09-192 as a novel therapeutic strategy in ER + breast cancers harboring FGFR1/2 somatic alterations. Treatment of ER+/FGFR1-amplified breast cancer cells and patient-derived xenografts with DGY-09-192 resulted in sustained degradation of FGFR1 in a proteasome-dependent manner and suppressed downstream signal transduction. The combination of DGY-09-192 and the ERα degrader fulvestrant resulted in complete cell growth arrest and tumor regression of ER+/FGFR1-amplified patients-derived xenografts. In addition, we tested the effect of DGY-09-192 on breast cancer cells expressing FGFR1(N546K) and FGFR2(K659E) hotspot kinase domain mutations as well as ER-negative breast cancer cells harboring FGFR2 gene amplification. Treatment with DGY-09-192 resulted in the degradation of mutant FGFR1/2 and blocked mutant receptor-induced signal transduction and antiestrogen resistance. Collectively, our study suggests that degradation of FGFR1/2, in combination with antiestrogens, can be leveraged as a therapeutic strategy in ER + breast cancers harboring FGFR1/2 driver alterations.