Role of ABL Kinase Signaling Networks in the Regulation of Cholesterol Homeostasis in Lung Cancer

Abstract Lung cancer continues to be the leading cause of cancer-related deaths globally, marked by a high incidence of metastatic disease and the development of resistance to treatment. Existing therapies for metastatic lung cancer lack an ability to elicit durable responses. Our laboratory has demonstrated that the Abelson (ABL) family of non- receptor tyrosine kinases promotes metastatic outgrowth of lung cancer cells in mouse models, and that inhibition of the ABL kinases disrupts metabolism and decreases tumor burden in vivo. To identify pathways that might synergize with ABL kinase inhibition to impede the growth of metastatic lung cancer cells, we performed a metabolically-focused CRISPR/Cas9 loss-of-function screen. This screen revealed that disrupting regulators of cholesterol homeostasis significantly sensitized metastatic lung cancer cells to cell death when combined with sub-therapeutic doses of allosteric ABL kinase inhibitors. The goal of this proposal is to investigate the role of ABL kinase signaling in cholesterol homeostasis in metastatic lung cancer, thereby uncovering novel exploitable vulnerabilities to improve treatment strategies. I will use CRISPR technology, pharmacological inhibitors, and mouse models of metastasis to evaluate the effectiveness of targeting cholesterol pathways in combination with the ABL kinases to impair lung cancer growth and metastasis.