Pık3ca mutant meme kanserlerinde alpelisib (Byl-719)-fulvestrant aracılı büyüme engellemesine direnç oluşturabilecek sinyal ağı etkinliklerinin belirlenmesi

Luminal A breast cancer, characterised by hormone receptor positivity and human epidermal growth factor receptor 2 negativity, represents approximately 70% of all reported cases of breast cancer. Mutations in components of the PI3K pathway, particularly p110 and PTEN, are commonly observed subsequent to p53 mutations in these cancers. Consequently, PI3K inhibitors are employed to treat breast tumours characterised by PI3KCA mutations. Nevertheless, inhibiting the PI3K pathway may give rise to the activation of other signalling pathways, hence inducing the development of drug resistance. The objective of this study is to examine the potential activation of pathways associated with the FDA-approved combined use of Alpelisib (BYL-719) and Fulvestrant in the treatment of PIK3CA mutant breast cancer. In this study, MCF7 and T47D cell lines developed acquired resistance to the Alpelisib/Fulvestrant combination. The resistant cells were then subjected to comparative transcriptome analysis to identify putative resistance networks. Our results implicate various components of the MAPK pathway as a potential resistance factor in both cellular models. We also corroborated these results via immunoblot analysis of the respective signalling cascades. Therefore, we assessed the potency of the combination of Pemigatinib, an FGFR inhibitor and alpelisib and have shown that this combination is successful in inhibiting the growth of the resistant cell lines. We also supported our findings by performing 3D growth assays with this combination. The findings of our study will contribute to the advancement of therapeutic strategies for luminal A breast cancer, particularly in the context of Alpelisib/Fulvestrant drug resistance.