Efficacy of a Covalent ERK1/2 Inhibitor, CC-90003, in KRAS-Mutant Cancer Models Reveals Novel Mechanisms of Response and Resistance
| Autor: | Carmen Maria Barnes, Ellen Filvaroff, Shi Tao, Mehnaz Malek, Gordon L. Bray, Winfried Elis, Yumin Dai, Konstantinos Mavrommatis, Lixin Qiao, Terri Jones, Ida Aronchik, Beebe Lisa, Matt Labenski |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Cancer Research MAP Kinase Signaling System Colorectal cancer Mutant Mice Nude medicine.disease_cause Proto-Oncogene Proteins p21(ras) Mice 03 medical and health sciences 0302 clinical medicine Cell Line Tumor medicine Animals Humans Lung cancer Molecular Biology Mutation Chemistry Cancer medicine.disease 030104 developmental biology Oncology Docetaxel Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Female KRAS medicine.drug |
| Zdroj: | Molecular Cancer Research. 17:642-654 |
| ISSN: | 1557-3125 1541-7786 |
| DOI: | 10.1158/1541-7786.mcr-17-0554 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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