Editors' ChoiceCancer

New MEK-anisms for Targeted Therapies

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Science Translational Medicine  28 Aug 2013:
Vol. 5, Issue 200, pp. 200ec141
DOI: 10.1126/scitranslmed.3007310

Mutations in BRAF and KRAS are common in many tumor types. Activating mutations in either molecule can trigger aberrant signaling via the mitogen-activated protein kinase (MAPK) pathway, resulting in unregulated cell growth and proliferation. Often depicted as a linear pathway sequentially linking RAS, RAF, MAPK kinase (MEK), and extracellular signal–regulated kinase (ERK), this pathway is actually more like a tangled web of feedback loops. Hatzivassiliou and colleagues shed new light on why, despite sharing a common signaling pathway, tumors with KRAS and BRAF mutations may respond differently to MEK inhibitors (MEKis).

The authors begin with the observation that KRAS-mutant and BRAF-mutant tumors have disparate sensitivities to some, but not all, MEKis. Specifically, the authors found that the MEKi GDC-0973 is a potent inhibitor of BRAF-mutant tumors but has poor activity in KRAS-mutant tumors. In contrast, two other MEKis (GDC-0623 and G-573) have similar activity in KRAS- and BRAF-mutant tumors. This finding is true for tumor cells grown in culture as well as tumor cells transplanted into mice. How can these differences be explained? To mechanistically untangle the signaling pathways that explain this observation, Hatzivassiliou et al. tested how each drug altered the levels of phosphorylated (activated) MEK in each tumor type. Through a series of experiments, they found that the most active MEKi in KRAS-mutant tumors were able to block phosphorylation of MEK by wild-type RAF via interaction with a key amino acid (S212) on MEK. Conversely, the MEKi that worked best in the BRAF-mutant tumors appeared to most potently bind an activated form of MEK, which may be relatively specific to or abundant in these tumors.

Altogether, the “MEK-anistic” data from Hatzivassiliou et al. suggest that specific MEK inhibitors may have superior or inferior clinical activity, depending on the type of mutation (KRAS or BRAF) present. These predictions need to be tested clinically; if correct, these concepts could further refine the clinical use of targeted inhibitors for cancer.

G. Hatzivassiliou et al., Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers. Nature, published online 11 August 2013 (10.1038/nature12441). [PubMed]

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