Targeting metabolic vulnerability in mitochondria conquers MEK inhibitor resistance in KRAS-mutant lung cancer

Juanjuan Feng; Zhengke Lian; Xinting Xia; Yue Lu; Kewen Hu; Yunpeng Zhang; Yanan Liu; Longmiao Hu; Kun Yuan; Zhenliang Sun; Xiufeng Pang

doi:10.1016/j.apsb.2022.10.023

Targeting metabolic vulnerability in mitochondria conquers MEK inhibitor resistance in KRAS-mutant lung cancer

Acta Pharm Sin B. 2023 Mar;13(3):1145-1163. doi: 10.1016/j.apsb.2022.10.023. Epub 2022 Oct 28.

Authors

Juanjuan Feng^{1

2}, Zhengke Lian¹, Xinting Xia¹, Yue Lu¹, Kewen Hu³, Yunpeng Zhang¹, Yanan Liu¹, Longmiao Hu¹, Kun Yuan¹, Zhenliang Sun², Xiufeng Pang¹

Affiliations

¹ Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
² Joint Center for Translational Medicine, Southern Medical University Affiliated Fengxian Hospital, Shanghai 201499, China.
³ Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.

Abstract

MEK is a canonical effector of mutant KRAS; however, MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers. Here, we identified mitochondrial oxidative phosphorylation (OXPHOS) induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer (NSCLC) resistance to the clinical MEK inhibitor trametinib. Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment, satisfying their energy demand and protecting them from apoptosis. As molecular events in this process, the pyruvate dehydrogenase complex (PDHc) and carnitine palmitoyl transferase IA (CPTIA), two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation. Importantly, the co-administration of trametinib and IACS-010759, a clinical mitochondrial complex I inhibitor that blocks OXPHOS, significantly impeded tumor growth and prolonged mouse survival. Overall, our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.

Keywords: Carnitine palmitoyl transferase IA; Drug resistance; KRAS-mutant lung cancer; MEK inhibitors; Metabolic rewiring; Mitochondrial oxidative phosphorylation; Pyruvate dehydrogenase complex.