Combined inhibition of G12C-mutant KRAS, mTOR and IGF1R for NSCLC

INDICATION: Non-small cell lung cancer (NSCLC)

Triple therapy with KRAS-G12C, mTOR and IGF1R inhibitors could treat KRAS G12C-mutant NSCLC. Whole genome screening of an shRNA library for targets whose inhibition enhanced the anti-tumor effects of MEK inhibitor Mekinist trametinib and the IGF1R inhibitor linsitinib in KRAS-mutant NSCLC cell line cultures showed inhibition of the mTOR pathway potentiates the effects of Mekinist and linsitinib. However, since combined inhibition of mTOR and MEK has been associated with unacceptable adverse effects in the clinic, the researchers replaced Mekinist with a tool inhibitor of G12C-mutant KRAS, and combined it with linsitinib and the mTOR inhibitor Afinitor everolimus. In two human NSCLC cell lines harboring the G12C mutation, the three drugs completely inhibited growth for up to 17 days. In three xenograft mouse models of KRAS G12C-mutant NSCLC, the triple therapy reduced tumor growth compared with either the G12C-mutant KRAS inhibitor alone or the linsitinib and Afinitor combo...