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Autophagy Inhibition Sensitizes Liver Kinase B1 (LKB1)‐Deficient Kras‐Driven Lung Tumors to MEK Inhibitor Trametinib
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, me...
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Published in: | The FASEB journal 2021-05, Vol.35 (S1), p.n/a, Article fasebj.2021.35.S1.03539 |
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Main Authors: | , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | 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, metastases and resistance to standard chemotherapy as well as immunotherapy. Thus, identifying a novel treatment for patients harboring co‐mutations in LKB1 and KRAS is urgently needed. Autophagy degrades and recycles the building blocks for cancer cells to survive metabolic challenges. Using genetically engineered mouse models (GEMMs), we have previously demonstrated 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. To further value our discoveries in clinical translational ability, we treated mouse lung tumor‐derived cell lines (TDCLs) with FDA‐approved autophagy inhibitor hydroxychloroquine (HCQ) and found that KL TDCLs were much sensitive to HCQ‐induced cell death compared with KP TDCLs. Furthermore, a combination treatment of HCQ with mitogen‐activated protein kinase kinase (MAPKK/MEK) inhibitor Trametinib showed synergistic anti‐proliferative effects in KL TDCLs, but not in KP TDCLs. To elucidate the underlying mechanism of increased sensitivity of KL TDCLs to Trametinib by autophagy ablation, we performed metabolomic profiling of KL TDCLs with Trametinib, HCQ, or combination treatment. We found that several glycolytic and TCA cycle intermediates, amino acids, and ATP levels were significantly upregulated upon treatment with Trametinib, which were significantly reduced by the combination treatment. In addition, we found that the combination treatment significantly reduced mitochondrial membrane potential, basal respiration as well as ATP production in KL TDCLs compared with the single agents. However, these effects were not observed 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. Finally, we performed in vivo tumor assay using allograft mouse models and GEMMs to validate our in vitro observations. We found anti‐tumor synergistic effects of the combination treatmen |
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ISSN: | 0892-6638 1530-6860 |
DOI: | 10.1096/fasebj.2021.35.S1.03539 |