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Clin Cancer Res. 2014 Aug 1;20(15):3921-30. doi: 10.1158/1078-0432.CCR-13-1762. Epub 2014 Jun 3.

A RAS renaissance: emerging targeted therapies for KRAS-mutated non-small cell lung cancer.

Author information

1
Department of Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts;
2
The Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College, New York, New York; and.
3
Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven, New Haven, Connecticut roy.herbst@yale.edu.

Abstract

Of the numerous oncogenes implicated in human cancer, the most common and perhaps the most elusive to target pharmacologically is RAS. Since the discovery of RAS in the 1960s, numerous studies have elucidated the mechanism of activity, regulation, and intracellular trafficking of the RAS gene products, and of its regulatory pathways. These pathways yielded druggable targets, such as farnesyltransferase, during the 1980s to 1990s. Unfortunately, early clinical trials investigating farnesyltransferase inhibitors yielded disappointing results, and subsequent interest by pharmaceutical companies in targeting RAS waned. However, recent advances including the identification of novel regulatory enzymes (e.g., Rce1, Icmt, Pdeδ), siRNA-based synthetic lethality screens, and fragment-based small-molecule screens, have resulted in a "Ras renaissance," signified by new Ras and Ras pathway-targeted therapies that have led to new clinical trials of patients with Ras-driven cancers. This review gives an overview of KRas signaling pathways with an emphasis on novel targets and targeted therapies, using non-small cell lung cancer as a case example.

PMID:
24893629
PMCID:
PMC5369356
DOI:
10.1158/1078-0432.CCR-13-1762
[Indexed for MEDLINE]
Free PMC Article

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