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