CCR FOCUS From the Editor

Targeting RAS: The Elusive Prize This CCR Focus examines a prized target in oncology—inhibition of RAS, the GTPase signaling protein known as a molecular signaling switch and found to be mutated in many common cancers. These mutations, typically in one of three key hotspots, keep the protein always on, signaling proliferation and survival. This CCR Focus examines the intense quest under way to develop a molecule or therapeutic strategy that will inhibit RAS. The articles, guided by Guest Editor Frank McCormick, discuss various aspects of targeting RAS: *




Downward discusses "synthetic lethal" approaches to RAS inhibition. Marcus and Mattos forecast direct inhibition of the "undruggable target." Cox, Der, and Philips revisit blocking its critical membrane attachments. Kimmelman offers RAS metabolic reprogramming as a therapeutic target.

Together, these articles demonstrate a multipronged effort to block RAS, known for over 30 years to be mutated in cancer, and express cautious optimism that it is just a matter of time before we can affect RAS activity in human cancer. After reading this CCR Focus, we no longer ask whether we "will ever have" an agent to inhibit aberrant RAS function in the clinic. Rather, we now may ask "how much benefit" we can expect to achieve. That is a complex question and, as discussed by McCormick, depends in large part on whether cancer cells remain dependent on RAS. The discovery of imatinib for chronic myelogenous leukemia (CML) created a paradigm shift in cancer research that sent the community on a search for solitary molecular targets that could fundamentally alter cancer biology. Over time, the uniqueness of the CML story has become apparent: For most other mutated oncogenic targets, long-term disease control has not been achievable, despite the availability of effective inhibitors. We expect that RAS inhibitors will shrink tumors in some cell types bearing RAS mutations, but not in all. But in 2015 we recognize that there will likely not be a "one-size-fits-all" anti-RAS drug for all RAS-driven cancers. Given all we have learned as a community, summarized in Text Box 1, this class of drugs should be one that we develop rationally with appropriate trial designs, patient selection, and confirmation of effective RAS inhibition, so that even if only a subset of patients is to derive meaningful benefit, we will be able to identify and treat that subset. And, in so doing, we will have a clear return on a 35-year investment in basic science.

Text Box 1. Brief timeline of key milestones in RAS research 1964/1967: Harvey and Kirsten rat sarcoma viruses isolated 1979: RAS is a 21-kDa GDP- and GTP-binding protein 1981: Viral Hras and Kras genes have a normal human cellular counterpart 1982: HRAS and KRAS identified as activated oncogenes in human cancer cell lines 1982: Bladder cancer HRAS gene is activated by a codon 12 mutation 1983: KRAS and NRAS activating mutations identified in human cancer cell lines 1983: Mutant HRAS transformation of primary cells requires cooperating genes 1984: Mutant HRAS has defective intrinsic GTPase activity 1988: HRAS crystal structure determined 1989: RAS membrane association and function are dependent on farnesylation 1990: NF1 tumor suppressor gene encodes a RasGAP 1992: MEK signaling discovered 1993: Farnesyltransferase inhibitors (FTI) block growth of HRAS-transformed cells 1993: RAF identified as the first mammalian RAS effector 1994: PI3K identified as a RAS effector 1997: Alternative KRAS4B and NRAS prenylation discovered in presence of FTI 2005: The FDA's Oncologic Drugs Advisory Committee votes against approval of the FTI tipifarnib 2005: The FDA rejects tipifarnib 2008: Tumors with KRAS mutation do not benefit from the EGFR antibody cetuximab 2009: Synthetic lethal interactors of mutant KRAS are identified 2012: FDA approves KRAS mutation test as a companion diagnostic for cetuximab 2012: First direct inhibitor of KRAS protein function identified 2013: A direct inhibitor of a specific KRAS mutant protein (G12C) is identified 2015: Tipifarnib to be revisited in HRAS cancers

Susan E. Bates Deputy Editor, CCR Focus National Cancer Institute See all articles in this CCR Focus section, "Targeting RAS-Driven Cancers." Published online April 15, 2015. doi: 10.1158/1078-0432.CCR-14-2664 Ó2015 American Association for Cancer Research.

1796 Clin Cancer Res; 21(8) April 15, 2015

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Targeting RAS: The Elusive Prize Susan E. Bates Clin Cancer Res 2015;21:1796.

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Targeting RAS: The Elusive Prize.

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