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Cold Spring Harb Perspect Med DOI:10.1101/cshperspect.a031518

Synthetic Lethal Vulnerabilities in KRAS-Mutant Cancers.

Publication TypeJournal Article
Year of Publication2017
AuthorsAguirre, AJ, Hahn, WC
JournalCold Spring Harb Perspect Med
Date Published2017 Nov 03

KRAS is the most commonly mutated oncogene in human cancer. Most KRAS-mutant cancers depend on sustained expression and signaling of KRAS, thus making it a high-priority therapeutic target. Unfortunately, development of direct small molecule inhibitors of KRAS function has been challenging. An alternative therapeutic strategy for KRAS-mutant malignancies involves targeting codependent vulnerabilities or synthetic lethal partners that are preferentially essential in the setting of oncogenic KRAS. KRAS activates numerous effector pathways that mediate proliferation and survival signals. Moreover, cancer cells must cope with substantial oncogenic stress conferred by mutant KRAS. These oncogenic signaling pathways and compensatory coping mechanisms of KRAS-mutant cancer cells form the basis for synthetic lethal interactions. Here, we review the compendium of previously identified codependencies in KRAS-mutant cancers, including the results of numerous functional genetic screens aimed at identifying KRAS synthetic lethal targets. Importantly, many of these vulnerabilities may represent tractable therapeutic opportunities.


Alternate JournalCold Spring Harb Perspect Med
PubMed ID29101114