Not just gRASping at flaws: finding vulnerabilities to develop novel therapies for treating KRAS mutant cancers.
Bottom Line: Mutations in Kirsten rat-sarcoma (KRAS) are well appreciated to be major drivers of human cancers through dysregulation of multiple growth and survival pathways.Similar to many other non-kinase oncogenes and tumor suppressors, efforts to directly target KRAS pharmaceutically have not yet materialized.Fueling these efforts is our increased understanding into the biology driving KRAS mutant cancers, in particular the important pathways that mutant KRAS governs to promote survival.
Affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.Show MeSH
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Mentions: We have recently showed KRAS mutant colorectal cancers are particularly vulnerable to simultaneous inhibition of the BCL-2 anti-apoptotic proteins BCL-2, BCL-XL and MCL-1.44 Pure mTORC catalytic site inhibitors downregulated MCL-1 in KRAS mutant colorectal cancers, and targeting KRAS with shRNA similarly reduced mTORC1 signaling and MCL-1 levels, suggesting MCL-1 to be a vital KRAS-effector molecule in these cancers. When combined with the BCL-2/BCL-XL inhibitor navitoclax, the mTORC1/2 inhibitor AZD8055 induced tumor regressions in KRAS mutant human colorectal cancer xenografts and Kras mutant genetically engineered mouse models of colorectal cancers. In all, this study provides the rationale to use mTORC inhibitors in combination with BCL-2/BCL-XL inhibitors in KRAS mutant colorectal cancers. Altogether, these data mark the apoptotic machinery as an attractive target to treat KRAS mutant cancers (Fig.2).
Affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.