1. Academic Validation
  2. Inhibition of autophagy and MEK promotes ferroptosis in Lkb1-deficient Kras-driven lung tumors

Inhibition of autophagy and MEK promotes ferroptosis in Lkb1-deficient Kras-driven lung tumors

  • Cell Death Dis. 2023 Jan 26;14(1):61. doi: 10.1038/s41419-023-05592-8.
Vrushank Bhatt 1 Taijin Lan 1 Wenping Wang 1 Jerry Kong 1 Eduardo Cararo Lopes 1 Jianming Wang 1 Khoosheh Khayati 1 Akash Raju 1 Michael Rangel 1 Enrique Lopez 1 Zhixian Sherrie Hu 1 Xuefei Luo 1 Xiaoyang Su 1 2 Jyoti Malhotra 1 2 Wenwei Hu 1 3 Sharon R Pine 1 2 3 Eileen White 1 4 5 Jessie Yanxiang Guo 6 7 8
Affiliations

Affiliations

  • 1 Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA.
  • 2 Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA.
  • 3 Department of Pharmacology, Rutgers University, Piscataway, NJ, 08903, USA.
  • 4 Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ, 08854, USA.
  • 5 Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, 08540, USA.
  • 6 Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA. yanxiang@cinj.rutgers.edu.
  • 7 Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA. yanxiang@cinj.rutgers.edu.
  • 8 Department of Chemical Biology, Rutgers Ernest Mario School of Pharmacy, Piscataway, NJ, 08854, USA. yanxiang@cinj.rutgers.edu.
Abstract

LKB1 and KRAS are the third most frequent co-mutations detected in non-small cell lung Cancer (NSCLC) and cause aggressive tumor growth. Unfortunately, treatment with RAS-RAF-MEK-ERK pathway inhibitors has minimal therapeutic efficacy in LKB1-mutant KRAS-driven NSCLC. Autophagy, an intracellular nutrient scavenging pathway, compensates for Lkb1 loss to support Kras-driven lung tumor growth. Here we preclinically evaluate the possibility of Autophagy inhibition together with MEK inhibition as a treatment for Kras-driven lung tumors. We found that the combination of the Autophagy Inhibitor hydroxychloroquine (HCQ) and the MEK Inhibitor Trametinib displays synergistic anti-proliferative activity in KrasG12D/+;Lkb1-/- (KL) lung Cancer cells, but not in KrasG12D/+;p53-/- (KP) lung Cancer cells. In vivo studies using tumor allografts, genetically engineered mouse models (GEMMs) and patient-derived xenografts (PDXs) showed anti-tumor activity of the combination of HCQ and Trametinib on KL but not KP tumors. We further found that the combination treatment significantly reduced mitochondrial membrane potential, basal respiration, and ATP production, while also increasing lipid peroxidation, indicative of Ferroptosis, in KL tumor-derived cell lines (TDCLs) and KL tumors compared to treatment with single agents. Moreover, the reduced tumor growth by the combination treatment was rescued by Ferroptosis inhibitor. Taken together, we demonstrate that Autophagy upregulation in KL tumors causes resistance to Trametinib by inhibiting Ferroptosis. Therefore, a combination of Autophagy and MEK inhibition could be a novel therapeutic strategy to specifically treat NSCLC bearing co-mutations of LKB1 and KRAS.

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