Combined inhibition of KRASG12C and mTORC1 kinase produces a synergistic effect in the treatment of non-small cell lung cancer (NSCLC).

The combined inhibition of KRASG12C and mTORC1 kinase has emerged as a promising strategy for treating non-small cell lung cancer (NSCLC), particularly in cases where KRASG12C mutations are present. 

KRASG12C mutations are common in NSCLC and current treatments with inhibitors like sotorasib and adagrasib are not fully effective. The research demonstrates that while KRASG12C inhibitors effectively suppress the ERK pathway, they show variable inhibition of the PI3K/mTOR pathway, which plays a crucial role in cancer cell survival.

Key findings of this study:

Combining KRASG12C inhibitors with mTORC1 kinase inhibitors results in more potent suppression of Cyclin D1 expression and cap-dependent translation, leading to a stronger antitumor response than using either inhibitor alone.

This combination causes durable tumor regressions in KRASG12C-dependent NSCLC models and significantly induces cell death by upregulating BIM (a pro-apoptotic protein) and inhibiting MCL-1 (an anti-apoptotic protein).

The study also highlights that mTORC1 inhibition by itself reduces MCL-1 levels, but only in combination with KRASG12C inhibition does it lead to significant apoptosis.

This combined inhibition blocks Cyclin D1 at both transcriptional and translational levels, which is critical for cell cycle arrest and preventing cancer cell proliferation.

Targeting both the ERK and PI3K/mTOR pathways may be an effective strategy for treating KRASG12C-mutant lung cancers, as each pathway compensates for the inhibition of the other.

Reference

Kitai, Hidenori & Choi, Philip & Yang, Yu & Boyer, Jacob & Whaley, Adele & Pancholi, Priya & Thant, Claire & Reiter, Jason & Chen, Kevin & Markov, Vladimir & Taniguchi, Hirokazu & Yamaguchi, Rui & Ebi, Hiromichi & Evans, James & Jiang, Jingjing & Lee, Bianca & Wildes, David & Stanchina, Elisa & Smith, Jacqueline & Rosen, Neal. (2024). Combined inhibition of KRAS and mTORC1 kinase is synergistic in non-small cell lung cancer. Nature Communications. 15. 10.1038/s41467-024-50063-z.