Abstract
As a critical signaling node, ERK1/2 are attractive drug targets, particularly in tumors driven by activation of the 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 (PDX) model of colorectal cancer. 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.
Highlights
The MAPK signal transduction cascade, consisting of RAS/RAF/ MEK/ERK, is activated in a variety of cancers including melanoma, colorectal cancer, pancreatic adenocarcinoma (PDAC), and lung cancer [1]
Subsequent studies have shown that resistance to BRAF inhibition in BRAF-mutant colorectal cancer is largely attributable to EGFR-mediated reactivation of signaling through the MAPK pathway [4, 5]
Cell culture All cell lines used in this study were obtained from the American Type Culture Collection (ATCC) and were used for experiments within 15 passages of authentication
Summary
The MAPK signal transduction cascade, consisting of RAS/RAF/ MEK/ERK, is activated in a variety of cancers including melanoma, colorectal cancer, pancreatic adenocarcinoma (PDAC), and lung cancer [1]. Critical nodes of this pathway, BRAF, MEK1/2, and ERK1/2, have been extensively explored as potential therapeutic targets [1]. The response rate of patients with V600E BRAF–mutant metastatic melanoma to Vemurafenib was approximately 80% 2), the response rate of patients with V600E BRAF–mutant colorectal cancer was approximately 5% Despite robust initial responses in BRAF-mutant melanoma patients with prolonged and deep inhibition of the target [6], response is limited to 2 to 18 months [7].
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