RT Journal Article SR Electronic T1 Discovery of a Novel ERK Inhibitor with Activity in Models of Acquired Resistance to BRAF and MEK Inhibitors JF Cancer Discovery JO CANCER DISCOVERY FD American Association for Cancer Research SP 742 OP 750 DO 10.1158/2159-8290.CD-13-0070 VO 3 IS 7 A1 Morris, Erick J. A1 Jha, Sharda A1 Restaino, Clifford R. A1 Dayananth, Priya A1 Zhu, Hugh A1 Cooper, Alan A1 Carr, Donna A1 Deng, Yongi A1 Jin, Weihong A1 Black, Stuart A1 Long, Brian A1 Liu, Jenny A1 DiNunzio, Edward A1 Windsor, William A1 Zhang, Rumin A1 Zhao, Shuxia A1 Angagaw, Minilik H. A1 Pinheiro, Elaine M. A1 Desai, Jagdish A1 Xiao, Li A1 Shipps, Gerald A1 Hruza, Alan A1 Wang, James A1 Kelly, Joe A1 Paliwal, Sunil A1 Gao, Xiaolei A1 Babu, Boga Sobhana A1 Zhu, Liang A1 Daublain, Pierre A1 Zhang, Ling A1 Lutterbach, Bart A. A1 Pelletier, Marc R. A1 Philippar, Ulrike A1 Siliphaivanh, Phieng A1 Witter, David A1 Kirschmeier, Paul A1 Bishop, W. Robert A1 Hicklin, Daniel A1 Gilliland, D. Gary A1 Jayaraman, Lata A1 Zawel, Leigh A1 Fawell, Stephen A1 Samatar, Ahmed A. YR 2013 UL http://cancerdiscovery.aacrjournals.org/content/3/7/742.abstract AB 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