ABSTRACT
Targeting mitochondrial metabolism has emerged as a treatment option for cancer patients. The ABL tyrosine kinases promote metastasis, and enhanced ABL signaling is associated with a poor prognosis in lung adenocarcinoma patients. Here we show that ABL kinase allosteric inhibitors impair mitochondrial integrity and decrease oxidative phosphorylation. To identify metabolic vulnerabilities that enhance this phenotype, we utilized a CRISPR/Cas9 loss-of-function screen and identified HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway and target of statin therapies, as a top-scoring sensitizer to ABL inhibition. Combination treatment with ABL allosteric inhibitors and statins decreases metastatic lung cancer cell survival in vitro in a synergistic manner. Notably, combination therapy in mouse models of lung cancer brain metastasis and therapy resistance impairs metastatic colonization with a concomitant increase in animal survival. Thus, metabolic combination therapy might be effective to decrease metastatic outgrowth, leading to increased survival for lung cancer patients with advanced disease.
Subject(s)
Apoptosis/drug effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Lung Neoplasms/drug therapy , Oncogene Proteins v-abl/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Signal Transduction/drug effects , Allosteric Regulation/drug effects , Allosteric Regulation/genetics , Animals , Apoptosis/genetics , Cell Line, Tumor , Drug Synergism , Humans , Lung Neoplasms/enzymology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Mice, Nude , Neoplasm Metastasis , Oncogene Proteins v-abl/genetics , Oncogene Proteins v-abl/metabolism , Signal Transduction/genetics , Xenograft Model Antitumor AssaysABSTRACT
The ABL kinases, ABL1 and ABL2, promote tumor progression and metastasis in various solid tumors. Recent reports have shown that ABL kinases have increased expression and/or activity in solid tumors and that ABL inactivation impairs metastasis. The therapeutic effects of ABL inactivation are due in part to ABL-dependent regulation of diverse cellular processes related to the epithelial to mesenchymal transition and subsequent steps in the metastatic cascade. ABL kinases target multiple signaling pathways required for promoting one or more steps in the metastatic cascade. These findings highlight the potential utility of specific ABL kinase inhibitors as a novel treatment paradigm for patients with advanced metastatic disease. Video abstract.