Discovery of a Novel ERK Inhibitor with Activity in Models of Acquired Resistance to BRAF and MEK Inhibitors
| Autor: | Shuxia Zhao, Paul Kirschmeier, Ulrike Philippar, Li Xiao, Wang James J-S, Boga Sobhana Babu, Pierre Daublain, Phieng Siliphaivanh, Priya Dayananth, Clifford Restaino, Donna Carr, Lata Jayaraman, Xiaolei Gao, Marc Pelletier, Ling Zhang, Bart Lutterbach, Erick J. Morris, Stuart Black, Rumin Zhang, Weihong Jin, Ahmed A. Samatar, Joe Kelly, Daniel J. Hicklin, Alan B. Cooper, Leigh Zawel, Liang Zhu, Brian Long, Elaine M. Pinheiro, Hugh Y. Zhu, Sharda Jha, Stephen Fawell, Sunil Paliwal, D. Gary Gilliland, Jenny Liu, William T. Windsor, David J. Witter, Edward DiNunzio, Yongi Deng, W. Robert Bishop, Minilik Angagaw, Desai Jagdish A, Alan Hruza, Gerald W. Shipps |
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| Rok vydání: | 2013 |
| Předmět: |
Proto-Oncogene Proteins B-raf
MAPK/ERK pathway Neuroblastoma RAS viral oncogene homolog Pharmacology medicine.disease_cause Cell Line Tumor Neoplasms medicine Humans Extracellular Signal-Regulated MAP Kinases Protein kinase A Protein Kinase Inhibitors neoplasms Cell Proliferation Kinase Cell growth Chemistry Melanoma MAP Kinase Kinase Kinases medicine.disease Oncology Drug Resistance Neoplasm Mutation KRAS Signal transduction Signal Transduction |
| Zdroj: | Cancer Discovery. 3:742-750 |
| ISSN: | 2159-8290 2159-8274 |
| DOI: | 10.1158/2159-8290.cd-13-0070 |
| Popis: | The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the mitogen-activated protein kinase (MAPK) pathway. Selective BRAF and MAP-ERK kinase (MEK) inhibitors have shown clinical efficacy in patients with melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the extracellular signal-regulated kinase (ERK) signaling pathway. Here, we describe the identification and characterization of SCH772984, a novel and selective inhibitor of ERK1/2 that displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency in tumor cells with mutations in BRAF, NRAS, or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor–resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. These data support the clinical development of ERK inhibitors for tumors refractory to MAPK inhibitors. Significance: BRAF and MEK inhibitors have activity in MAPK-dependent cancers with BRAF or RAS mutations. However, resistance is associated with pathway alterations resulting in phospho-ERK reactivation. Here, we describe a novel ERK1/2 kinase inhibitor that has antitumor activity in MAPK inhibitor-naïve and MAPK inhibitor-resistant cells containing BRAF or RAS mutations. Cancer Discov; 3(7); 742–50. ©2013 AACR. See related commentary by Nissan et al., p. 719 This article is highlighted in the In This Issue feature, p. 705 |
| Databáze: | OpenAIRE |
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