Targeting autophagy to increase the sensitivity of LKB1-deficient lung tumors to angiogenesis inhibitor

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ABSTRACT Lung cancer is the leading cancer killer worldwide, with non-small cell lung cancer (NSCLC) accounting for more than 85% of these cases. KRAS and LKB1 are the two most frequent mutations detected in lung cancer patients. Lung cancer patients bearing co-mutations of KRAS and LKB1 show increased aggressiveness, a high frequency of metastases, and resistance to all standard therapies. Cancer cells acquire nutrients from circulating blood. Angiogenesis inhibitors, which block the growth of blood vessels, have been used for lung cancer treatment. However, multiple preclinical as well as clinical studies have reported that LKB1 depletion confers resistance to angiogenesis inhibitors, regardless of whether or not receiving chemotherapy. One of acquired resistance to antiangiogenics stems from tumor adaptations by induction of metabolic symbiosis. Autophagy is a process that cell eats itself to generate building blocks, energy, and redox homeostasis, and for elimination of waste in response to metabolic stress, such as nutrient depletion. Many studies including our group have proved that in response to extracellular nutrient deprivation, cancer cells can scavenge nutrients through autophagy- mediated intracellular recycling for tumor growth, proliferation, survival, and malignancy. Therefore, simultaneously eliminating nutrient availability from both intracellular and extracellular sources could be an innovative strategy for a successful cancer treatment. In particular, we recently demonstrated that autophagy is upregulated in Kras-mutant Lkb1-deficient (KL) lung tumor and autophagy inhibition is synthetically lethal in KL- mediated tumorigenesis. Moreover, anti-tumor effect by autophagy ablation is much more profound in Lkb1- deficient KL lung tumor than Lkb1 wild type (WT) KP (Kras-mutant p53-deficient) lung tumor. Based on above rationale and preliminary studies, we formed central hypothesis: autophagy-mediated intracellular recycling compensates for nutrient deprivation caused by angiogenesis inhibitor to support the survival and growth of KL lung tumor. We will: 1) determine the role and mechanism of cell-autonomous autophagy in conferring resistance of KL lung tumor to angiogenesis inhibitor; and 2) Determine if targeting autophagy can sensitize Lkb1-deficient KL lung tumor, but not Lkb1-WT KP lung tumor, to angiogenesis inhibitor. Our study will determine if LKB1 mutations could be explored as a predictive biomarker for precision lung cancer therapy using the combination of autophagy inhibitor and angiogenesis inhibitor. Once our hypothesis is confirmed in preclinical mouse models, the novel therapy of autophagy inhibitor hydroxychloroquine combined with angiogenesis inhibitor Bevacizumab can be naturally and immediately translated into clinical trials for treating lung cancer patients harboring co- mutations of KRAS and LKB1.