Indication

Target/marker/pathway

Summary

Licensing status

Publication and contact information

Cancer

Melanoma

MAP kinase 1 (MAPK1; ERK-2); MAPK3 (ERK-1)

Studies in human tissue and cell culture suggest inhibiting ERK-1 and 2 could be useful for treating melanoma resistant to a combination of BRAF and MEK inhibitors. Whole-exome sequencing of recurring tumors in patients treated with BRAF inhibitors identified a number of mutations and gene duplications in the MAPK pathway in tumors after the onset of resistance that were absent prior to treatment. In a subset of patients with acquired resistance to a combination of BRAF and MEK inhibitors, sequencing identified activating mutations in MAP kinase kinase 2 (MAP2K2; MEK2). In cell culture, a small molecule ERK-1 and 2 inhibitor decreased growth of the MEK2-mutant cells compared with vehicle. Next steps could include testing a triple combination of BRAF, MEK and ERK-1 and 2 inhibitors in mouse models of melanoma.
Tafinlar dabrafenib (GSK2118436) from GlaxoSmithKline plc and Zelboraf vemurafenib from Roche and Daiichi Sankyo Co. Ltd. are BRAF inhibitors marketed to treat BRAF-mutant melanoma.
GSK also markets Mekinist trametinib (GSK1120212), a small molecule MEK inhibitor, to treat BRAF-mutant melanoma.
At least 14 other companies have MEK inhibitors in Phase III or earlier testing to treat various cancers.
Aeterna Zentaris Inc. has the phosphoinositide 3-kinase (PI3K) and ERK-1 and 2 inhibitor AEZS-136 in preclinical development for cancer (see The next battle line against melanoma, page 4).

SciBX 7(1); doi:10.1038/scibx.2014.12
Published online Jan. 9, 2014

Patent and licensing status undisclosed

Wagle, N. et al. Cancer Discov.; published online Nov. 21, 2013;
doi:10.1158/2159-8290.CD-13-0631
Contact: Jennifer A. Wargo, Harvard Medical School, Boston, Mass.
e-mail:

jwargo@mdanderson.org
Contact: Levi A. Garraway,
Dana-Farber Cancer Institute,
Boston, Mass.
e-mail:

levi_garraway@dfci.harvard.edu

Van Allen, E.M. et al. Cancer Discov.;
published online Nov. 21, 2013;
doi:10.1158/2159-8290.CD-13-0617
Contact: Dirk Schadendorf, University Hospital Essen, Essen, Germany
e-mail:

dirk.schadendorf@uk-essen.de
Contact: Levi A. Garraway,
Dana-Farber Cancer Institute,
Boston, Mass.
e-mail:

levi_garraway@dfci.harvard.edu