Abstract 2049: LKB1 regulates BH3-mimetics vulnerability of KRAS mutant non-small cell lung cancer by alternating mitochondrial apoptotic protein interactions
Authors: Li Chendi , Oh Audris , Nangia Varuna , Hata Aaron N. 
Published: August 2019

Abstract
Over 30% of lung adenocarcinomas harbor KRAS mutation. Despite progress in targeted therapies for specific genetic subsets of lung cancer (e.g. EGFR or ALK), there are no clinically effective targeted therapies for KRAS non-small cell lung cancer (NSCLC). Interpatient heterogeneity of KRAS mutant lung cancers, with large variability in co-occurring mutations, may contribute to its refractory phenotype. Specifically, KRAS mutant lung cancers with concurrent loss of the tumor suppressor LKB1 (KRAS-LKB1) have increased metastatic frequency and resistance to chemotherapy in pre-clinical models, and these patients have poor responses to immune checkpoint inhibitor. Thus, there is a critical need to develop novel therapeutic approaches for this subset of NSCLC. Intrinsic resistance to apoptosis limits the efficacy of therapies targeting KRAS signaling. Previous studies reported BCL-2/BCL-XL + MEK inhibition can increase apoptotic responses of some KRAS mutant cancers. Recently, potent and selective inhibitors of MCL-1 have been developed, creating additional possibilities for targeting apoptotic machinery for cancers that dependent upon MCL-1 for survival.
We recently reported that novel MCL-1 inhibitor AMG-176 combined with MEK inhibitor trametinib can induce tumor regression in subsets of KRAS mutant NSCLC pre-clinical tumor models. In addition to commercially available cell lines, we established 20 patient-derived cell line/xenograft mouse model and showed that KRAS-LKB1 cell lines are particularly sensitive to MEK + MCL1 inhibition with high synergy score. Moreover, restoring LKB1 expression in LKB1-/- cell lines hampers the synergy and blocks mitochondrial depolarization and apoptosis. BH3-profiling reveals high dependency on MCL-1 in KRAS-LKB1 cell lines. We reported that trametinib increase intercellular Bim (pro-apoptotic protein) and subsequent loading of Bim onto pro-survival proteins BCL-XL and/or MCL1. MCL1 inhibitor releases Bim from MCL1 and initiates the apoptotic cascade. Interestingly, trametinib induces preferential sequestration of Bim by MCL-1 in KRAS-LKB1 models. Restoration of LKB1 in LKB1-/- cell lines reduces the trametinib-induced Bim:MCL-1 protein-protein interactions. Combined inhibition of MEK + MCL1 caused dramatic tumor regression in LKB1-deficient xenograft mouse models compared to LKB1-restored models.
Our results reveal fundamental insights into a novel role for LKB1 in the regulation of mitochondrial apoptosis and will lay a solid pre-clinical foundation for the clinical investigation of the MEK + MCL-1 inhibitor combination. Our data may also support using LKB1 as a genetic biomarker for guiding the selection of BH3 mimetics in targeting KRAS mutant NSCLC.
Citation Format: Chendi Li, Audris Oh, Varuna Nangia, Aaron N. Hata. LKB1 regulates BH3-mimetics vulnerability of KRAS mutant non-small cell lung cancer by alternating mitochondrial apoptotic protein interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2049.