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ABL allosteric inhibitors synergize with statins to enhance apoptosis of metastatic lung cancer cells

ABSTRACT: SUMMARY 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. Graphical Abstract In brief Metabolic reprogramming in tumors is an adaptation that generates vulnerabilities that can be exploited for developing new therapies. Here Luttman et al. identify synergism between ABL allosteric inhibitors and lipophilic statins to impair metastatic lung cancer cell outgrowth and colonization, leading to increased survival in mouse models of advanced disease.

SUBMITTER: Luttman J

PROVIDER: S-EPMC8579324 | biostudies-literature |

REPOSITORIES: biostudies-literature

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