Abstract 5265: Targeting mtDNA dynamics enhances immunogenicity and sensitizes KRAS mutant cancers to PD-1 blockade

Abstract Mitochondrial DNA (mtDNA) can stimulate an innate immune response that potentiates the efficacy of cancer immunotherapy. However, mtDNA-targeting therapy has not been developed to enhance this innate immune system in specific cancer subtypes efficiently. Here we discover that mtDNA is enriched in KRAS mutant tumors where the DNA sensor machinery cGAS-STING signaling is primed for innate immune activation. Intriguingly, MEK inhibitor induces cytosolic mtDNA release to potently activate the cGAS-STING signaling, which in turn induces PRKN-mediated mitophagy in response to mitochondrial stress in KRAS mutant cancer cells. During the process of mitophagy, PRKN, as an E3 ubiquitin ligase, degrades BAX protein and attenuates mitochondrial pore formation, which is essential for mtDNA efflux upon MEK inhibition. Combined MEK and mitophagy inhibitors efficiently stimulate type I IFNs in both mtDNA- and STING-dependent manners, and this combination enhances the efficacy of PD-1 blockade in Kras mutant murine syngeneic tumors. In the clinic, PRKN is associated with a ‘cold tumor’ phenotype among KRAS mutant tumors. Together, targeting mtDNA dynamics by co-inhibition of MEK and mitophagy represents a promising strategy to convert ‘cold to hot tumor’ in mtDNA-enriched KRAS mutant cancers. Citation Format: Kosuke Tanaka, Yasuki Adachi, Miyuki Yoshiya, Takuya Owari, Tomoko Yamamori-Morita, Akihiro Ohashi, Susumu Kobayashi, Shohei Koyama, Hiroyoshi Nishikawa. Targeting mtDNA dynamics enhances immunogenicity and sensitizes KRAS mutant cancers to PD-1 blockade abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5265.