İleri evre luminal a meme kanserinde alpelisib fulvestrant kombinasyon tedavisine direnç mekanizmalarının in vitro ve in vivo karakterizasyonu

Mutations in the PI3K pathway are prevalently observed in Luminal A-type breast cancer, characterized by HR positivity and HER2 negativity. While PI3K inhibitors, such as alpelisib, are FDA-approved for the treatment of PI3KCA-mutant breast cancers, PI3K pathway inhibition can activate compensatory signaling, leading to drug resistance. The objective of this study is to identify potential resistance mechanisms associated with the FDA-approved combination of alpelisib and fulvestrant in the treatment of advanced-stage PIK3CA-mutant breast cancer. In this context, MCF7 and T47D cell lines with acquired resistance to the alpelisib/fulvestrant combination were generated and subjected to comparative transcriptome analysis to identify potential resistance networks. Transcriptomic analysis revealed overactivation of FGFR signaling as a key mechanism of resistance. To elucidate the functional impact of FGFR-dependent resistance mechanisms, resistant cells and 3D tumor spheroid models were treated with the combination of alpelisib/pemigatinib, revealing synergistic growth-inhibitory activity of pemigatinib, an FDA-approved pan-FGFR inhibitor, when combined with alpelisib in alpelisib/fulvestrant-resistant cell lines and 3D tumor spheroids. Concurrent inhibition of the FGFR pathway and p110α led to sustained tumor regression in drug-resistant tumor xenografts in vivo. Overall, our study identifies FGFR signaling as a key mediator of resistance to combined alpelisib and fulvestrant treatment in PI3KCA-mutant luminal A breast cancer. These findings suggest that targeting the FGFR pathway in combination with PI3K inhibition may represent a potential strategy to overcome drug resistance in advanced-stage refractory luminal A breast cancer.