Exploiting Metabolic Vulnerabilities In Solid Tumors Treated With ABL Kinase Allosteric Inhibitors

Abstract

Metastases are common and devastating complications linked to ~90% of cancer deaths. Therapy-resistance is a major challenge for the treatment of cancer cell metastasis as metastatic cells metabolically rewire to survive cytotoxic therapies and adapt to new environments. Understanding and effectively targeting these metabolic changes opens an entirely new therapeutic avenue for combating cancer by defining cancer-related metabolic vulnerabilities. Using a CRISPR/Cas9 loss-of-function screen and RNA-sequencing analysis, the studies presented herein identify two metabolic vulnerabilities that arise following ABL allosteric inhibitor treatment to target metastatic and therapy-resistant cancer cells. First, we identify a novel combination therapy of ABL kinase allosteric inhibitors with lipophilic statins that impairs growth of clinically relevant therapy-resistant and brain metastatic lung cancer cells in vitro and in in vivo using mouse models. We found that ABL allosteric inhibitors impair mitochondria function without altering glycolytic capacity, leading to sensitization to statin therapeutics, and enhanced synergy to promote cancer cell death by combination therapy. Further, we found that ABL inhibitors are sensitized to statins due to the ability of statin therapeutics to inhibit the isoprenoid pathway, specifically protein geranylgeranylation. These results reveal a potential striking clinical benefit as synergy was not noted upon combination with standard of care therapeutics, gefitinib and docetaxel, and identify a new treatment strategy for patients refractory to first-line therapeutics or with metastases to difficult to treat organs like the brain. We have also characterized a novel ABL signaling axis as ABL inhibition was shown to deplete SLC7A11 protein levels in cancer cells. SLC7A11 is the catalytic subunit of system xCT and enables cystine import for cell detoxification and concomitant glutamate export. By depleting cancer cells of SLC7A11, cell detoxification processes are limited and excretion of toxic glutamate levels into the tumor microenvironment decrease. These data suggest that ABL regulation of this pathway could extend survival and relieve harmful symptoms in patients experiencing primary and secondary metastatic tumors. Collectively, our findings reveal metabolic vulnerabilities that can be targeted in cancer cells through treatment with ABL allosteric inhibitors, leading to improved patient survival and quality of life.