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Efficacy of a Covalent ERK1/2 Inhibitor, CC-90003, in KRAS Mutant Cancer Models Reveals Novel Mechanisms of Response and Resistance.

As a critical signaling node, extracellular signal-regulated kinases (ERK1/2) are attractive drug targets, particularly in tumors driven by activation of the Mitogen Activated Protein Kinase (MAPK) pathway. Utility of targeting the MAPK pathway has been demonstrated by clinical responses to inhibitors of MEK1/2 or RAF kinases in some mutant-BRAF activated malignancies. Unlike tumors with mutations in BRAF, those with mutations in KRAS (>30% of all cancers and >90% of certain cancer types) are generally not responsive to inhibitors of MEK1/2 or RAF. Here, a covalent ERK1/2 inhibitor, CC-90003 was characterized and shown to be active in preclinical models of KRAS mutant tumors. A unique occupancy assay was used to understand the mechanism of resistance in a KRAS mutant patient-derived xenograft model (PDX) of colorectal cancer (CRC). Finally, combination of CC-90003 with Docetaxel achieved full tumor regression and prevented tumor regrowth after cessation of treatment in a PDX model of lung cancer. This effect corresponded to changes in a stemness gene network, revealing a potential effect on tumor stem cell reprograming.

IMPLICATIONS: Here, a covalent ERK1/2 inhibitor (CC-90003) is demonstrated to have preclinical efficacy in models of KRAS mutant tumors, which present a therapeutic challenge for currently available therapies.

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