Supplementary Figures from Discovery of a Novel ERK Inhibitor with Activity in Models of Acquired Resistance to BRAF and MEK Inhibitors

Morris, Erick J.; Jha, Sharda; Restaino, Clifford R.; Dayananth, Priya; Zhu, Hugh; Cooper, Alan; Carr, Donna; Deng, Yongi; Jin, Weihong; Black, Stuart; Long, Brian; Liu, Jenny; DiNunzio, Edward; Windsor, William; Zhang, Rumin; Zhao, Shuxia; Angagaw, Minilik H.; Pinheiro, Elaine M.; Desai, Jagdish; Xiao, Li; Shipps, Gerald; Hruza, Alan; Wang, James; Kelly, Joe; Paliwal, Sunil; Gao, Xiaolei; Babu, Boga Sobhana; Zhu, Liang; Daublain, Pierre; Zhang, Ling; Lutterbach, Bart A.; Pelletier, Marc R.; Philippar, Ulrike; Siliphaivanh, Phieng; Witter, David; Kirschmeier, Paul; Bishop, W. Robert; Hicklin, Daniel; Gilliland, D. Gary; Jayaraman, Lata; Zawel, Leigh; Fawell, Stephen; Samatar, Ahmed A.

doi:10.1158/2159-8290.22530809.v1

21598290cd130070-sup-supplementary_figures_-_pdf_file_1385k.pdf (1.35 MB)

Supplementary Figures from Discovery of a Novel ERK Inhibitor with Activity in Models of Acquired Resistance to BRAF and MEK Inhibitors

journal contribution

posted on 2023-04-03, 20:49 authored by Erick J. Morris, Sharda Jha, Clifford R. Restaino, Priya Dayananth, Hugh Zhu, Alan Cooper, Donna Carr, Yongi Deng, Weihong Jin, Stuart Black, Brian Long, Jenny Liu, Edward DiNunzio, William Windsor, Rumin Zhang, Shuxia Zhao, Minilik H. Angagaw, Elaine M. Pinheiro, Jagdish Desai, Li Xiao, Gerald Shipps, Alan Hruza, James Wang, Joe Kelly, Sunil Paliwal, Xiaolei Gao, Boga Sobhana Babu, Liang Zhu, Pierre Daublain, Ling Zhang, Bart A. Lutterbach, Marc R. Pelletier, Ulrike Philippar, Phieng Siliphaivanh, David Witter, Paul Kirschmeier, W. Robert Bishop, Daniel Hicklin, D. Gary Gilliland, Lata Jayaraman, Leigh Zawel, Stephen Fawell, Ahmed A. Samatar

Supplementary Figures - PDF file 1385K, File contains Supplementary figures of resistant cell lines, proliferation assay of a panel of cell lines, TdF binding assay transcriptional out and kinome selectivity

History

ARTICLE ABSTRACT

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. 719This article is highlighted in the In This Issue feature, p. 705