LAUSR

For cancer cells to survive during ECM-detachment, they must inhibit anoikis and rectify metabolic deficiencies that cause non-apoptotic cell death. Previous studies in ECM-detached cells have linked non-apoptotic cell death to ROS generation, although the mechanistic underpinnings of this link remain poorly defined. Here, we uncover a novel role for receptor-interacting protein kinase-1 (RIPK1) in the modulation of mitochondrial ROS levels and cell viability during ECM-detachment. We find that RIPK1 activation during ECM-detachment results in the induction of PINK1-dependent mitophagy through a mechanism requiring the mitochondrial phosphatase PGAM5. As a consequence of mitophagy induction, ECM-detached cells experience diminished IDH2-mediated NADPH production in the mitochondria and the subsequent elevation in mitochondrial ROS levels leads to non-apoptotic cell death. Furthermore, we find that antagonizing RIPK1 or PGAM5 enhances tumor formation in vivo. Intriguingly, upon mining a meta-analysis of published lung cancer patient microarray data sets, we find that low RIPK1 expression in lung cancer patients correlates with decreased overall and progression-free survival. Thus, RIPK1-mediated induction of mitophagy may be an efficacious target for novel therapeutics aimed at specifically eliminating ECM-detached cancer cells and deterring tumor progression. Citation Format: Mark A. Hawk, Zachary T. Schafer. RIPK1-mediated induction of mitophagy compromises the viability of extracellular matrix-detached cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2410.