A novel PI3K/mTOR dual inhibitor XH002 exhibited robust antitumor activity in NSCLC.

NSCLC is a worldwide challenge due to its high incidence and poor survival. PI3K-Akt-mTOR (PAM) pathway is one of the major pathways that mediate receptor tyrosine kinases (RTKs) signalling transduction. Aberration in PAM pathway is indicated correlating with poor prognosis of NSCLC. In this article, we highlighted a 2-amino-4-methylquinazoline derivative XH002 as PI3K/mTOR dual inhibitor with outstanding antitumor efficacy. Briefly, XH002 significantly repressed proliferation of PI3KCA mutant and/or P-S6RP, P-RAS40 high expressed NSCLC cells. In vitro, XH002 decreased the phosphorylation of PAM pathway proteins in a dose-dependent and time-dependent way. Further investigation indicated that the cancer cells repression by XH002 derived from inducing cell cycle arrest in G1 phase. Moreover, XH002 remarkably inhibited tumour growth of EGFR-TKIs resistant NCI-H1975 xenograft model by blocking PAM pathway. In conclusion, XH002 is a potent oral PI3K/mTOR dual inhibitor that possesses excellent antitumor efficacy against PIK3CA mutant NSCLC, including which resistant to EGFR-TKIs treatments.