Inhibition of autophagy suppresses KRAS-driven non-small cell lung cancer
Lung cancer remains the leading cause of cancer-related mortality throughout the world, in part due to a lack of therapeutic options that target prevalent molecular alterations. Activating mutations in KRAS occur in 30% of lung adenocarcinomas, and lead to aggressive, untreatable disease, especially with concomitant loss of tumor suppressors such as TP53 or LKB1. Autophagy—the process by which cells remove damaged proteins and recycle nutrients—is an attractive target in KRAS-driven cancers, as studies have shown a reliance on autophagy for growth and survival, in part due to nucleotide metabolism. We hypothesize that autophagy inhibition in combination with DNA damaging agents could represent an effective therapy for KRAS-driven cancers. First, we tested an autophagy inhibitor (MRT-68921) in an isogenic setting where mutant KRAS was ectopically expressed in a H838 cells. In agreement with past studies, cell viability was significantly suppressed in the KRAS-driven isogenic compared to the wild-type cells when exposed to MRT-68921. We next sought to understand the role that the tumor suppressor LKB1 might play in the response to autophagy inhibition, as LKB1 associates with a number of autophagy related genes. In H2030 cells (mtKRAS, LKB1-), functional LKB1 was re-expressed. The re-expression of LKB1 was sufficient to significantly increase cell viability in KRAS-driven cancer cells exposed to autophagy inhibition compared to those with no LKB1. Next, we coupled autophagy inhibition to DNA damaging therapy (cisplatin, a standard-of-care chemotherapy in lung cancer) in KRAS-driven lung cancer cells. The combination of MRT-68921 and cisplatin reduced cell viability more than cisplatin alone across all molecular settings, with the combination being most effective in the context of mutant KRAS and LKB1 loss. Future directions will include understanding the molecular mechanisms by which KRAS and LKB1 effect autophagy inhibitors as well as optimizing combinations in an in vivo setting. Our results suggest that autophagy inhibition, coupled with commonly employed DNA damaging agents, could be particularly effective in fighting KRAS-driven cancers.