Piqray

Alpelisib is a class I phosphatidylinositol 3-kinase (PI3K) inhibitor with higher activity against PI3Kα than other members of class I PI3K. Class I PI3K lipid kinases are key components of the PI3K/AKT/mammalian target of rapamycin (mTOR) signalling pathway. Gain-of-function mutations in the gene encoding the catalytic α-subunit of PI3K (PIK3CA) lead to activation of PI3Kα manifested by increased lipid kinase activity, growth-factor independent activation of Akt-signaling, cellular transformation and the generation of tumours in preclinical models.In vitro, alpelisib treatment inhibited the phosphorylation of PI3K downstream targets Akt as well as its various downstream effectors in breast cancer cells and showed activity towards cell lines harboring a PIK3CA mutation.In vivo, alpelisib showed good tolerability as well as dose-and time-dependent inhibition of the PI3K/Akt pathway and dose-dependent tumour growth inhibition in relevant tumour xenograft models, including models of breast cancer.PI3K inhibition by alpelisib treatment has been shown to induce an increase in estrogen receptor (ER) transcription in breast cancer cells, therefore, sensitizing these cells to ER inhibition by fulvestrant treatment. Combination of alpelisib and fulvestrant demonstrated increased anti-tumour activity than either treatment alone in xenograft models derived from ER+, PIK3CA mutated breast cancer cell lines (MCF-7 and KPL1).