Role of autophagy in LKB1-deficient Kras-driven non-small cell lung cancer

Tumor suppressor liver kinase B1 (LKB1) activates 5’-adenosine monophosphate protein kinase (AMPK) and maintains energy homeostasis in response to energy crises. LKB1 and KRAS are the third most frequent co-mutations detected in non-small cell lung cancer (NSCLC), causing aggressive tumor growth. Treatment with RAS-RAF-MEK-ERK pathway inhibitors have minimal therapeutic efficacy in LKB1-mutant Kras-driven NSCLC but can form the basis for lung cancer combination therapies. Autophagy is a lysosomal-mediated self-cannibalization process that seizes, digests and metabolizes subcellular and macromolecules cellular organelles. We have previously reported that autophagy compensates for Lkb1 loss for Kras-driven lung tumorigenesis; loss of an autophagy essential gene Atg7 dramatically impaired tumor initiation and tumor growth in KrasG12D/+;Lkb1-/- (KL) lung tumors. This is in sharp contrast to Lkb1 wild-type (WT) (KrasG12D/+;p53-/- (KP)) tumors that are less sensitive to autophagy gene ablation. We further found that autophagy deficiency causes defective intracellular recycling, which limits amino acids (AAs) to support mitochondrial energy production in starved cancer cells and causes autophagy-deficient cells to be more dependent on fatty acid oxidation (FAO) for energy production, leading to reduced lipid reserve and energy crisis. Our findings strongly suggest that autophagy inhibition could be a strategy for treating LKB1-deficient lung tumors. However, targeting autophagy alone might be insufficient for the development of a potent cancer agent. We designed the concept of using a combination therapy of autophagy together with MEK inhibition as a strategy to developing potent lung cancer agents. The combination therapy displays synergistic anti-proliferative effects in KL TDCLs, but not in KP TDCLs. Similarly, we found that LKB1-mutant human lung cancer cell lines were much more sensitive to the combination treatment than LKB1 WT cells. Treatment with ferroptosis inhibitor Ferrostatin-1 rescued the cell death induced by the combination treatment. Furthermore, in vivo studies using allograft mouse models and GEMMs showed anti-tumor synergistic effects of the combination treatment in KL tumor growth, with no such effect in KP tumor growth. Taken together, our observations suggest that autophagy upregulation in Lkb1-deficient tumors cause resistance to Trametinib treatment by maintaining energy homeostasis and inhibiting ferroptosis to support KL cell survival. Therefore, a combination of autophagy and MEK inhibition could be a novel therapeutic strategy to specifically treat LKB1-deficient NSCLC.Ph.D.Includes bibliographical reference