Editors' ChoiceCancer

A new hope for KRAS mutant cancers

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Science Translational Medicine  21 Feb 2018:
Vol. 10, Issue 429, eaas8964
DOI: 10.1126/scitranslmed.aas8964

Abstract

c-RAF ablation in KRAS mutant lung tumors is highly efficacious, supporting the development of selective c-RAF inhibitors for clinical use.

KRAS is the most frequently mutated oncogene in human cancers, and strategies that repress its oncogenic properties are predicted to benefit a high number of patients. Unfortunately, the development of direct KRAS inhibitors remains elusive. As an alternative, several drugs that target KRAS downstream effectors, involved in MAPK and PI3K pathways, have been tested, but high toxicity has prevented their clinical implementation. In a recent study, Sanclemente et al. report that ablation of c-RAF, a KRAS effector, in KRAS mutant lung tumors leads to tumor regressions with minimal toxicity, indicating that the development of selective c-RAF inhibitors could represent a viable strategy for these intractable tumors.

To inhibit c-RAF in established Kras mutant lung tumors, the authors generated a genetically engineered mouse model that allowed control of the location and timing of tumor development and target ablation, mimicking clinical intervention. Briefly, intratracheal infection with adenoviruses expressing Flp recombinase enabled the expression of mutant Kras in the lung and subsequent development of lung adenocarcinomas, whereas at-will administration of tamoxifen led to ubiquitous expression of Cre recombinase and systemic elimination of the target protein. c-RAF ablation, but not b-RAF, in Kras mutant lung tumors caused widespread tumor regressions and significant increase in survival with negligible toxicity. Similar benefits were seen in advanced Kras mutant/p53 null lung adenocarcinomas. Surprisingly, analysis of lung tumors and cell lines indicated that the antitumor effects upon c-RAF ablation were MAPK-independent, explaining the limited toxicity. c-RAF inhibition in lung cancer patient-derived xenografts with shRNAs was also effective, confirming the clinical relevance of the findings.

These results warrant the clinical development of c-RAF inhibitors for the treatment of KRAS mutant cancers. The design of highly selective c-RAF inhibitors will be critical to ensure low toxicity. Moreover, testing the effect of c-RAF inhibition in additional KRAS mutant cancers, including pancreatic and colorectal, will be required to confirm broader applicability. Last, the authors advise that combination with other therapies may be needed to increase the therapeutic benefits of c-RAF inhibition. Taken together, targeting c-RAF may provide a new hope for the treatment of KRAS mutant cancers.

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