Thursday, January 9, 2014
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Protein kinase B (PKB; PKBA;
Studies in human tissue and
cell culture suggest antagonizing AKT signaling could be useful for treating BRAF inhibitor-resistant
melanoma. In 100 tumor biopsies from 44 patients with BRAF inhibitor-resistant
melanoma, activating mutations in a range of AKT pathway regulators,
including AKT itself, were found in 22% of resistant tumor biopsies. In cell
culture, tumor cells with activating AKT mutations had higher AKT pathway
signaling and greater survival in the presence of a BRAF inhibitor than
controls lacking the AKT mutations. Next steps include clinical testing of
AKT inhibitors in combination with inhibitors of BRAF or MAPK
signaling, another pathway implicated in BRAF inhibitor-resistant 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.
At least 12 companies including Roche and GSK have AKT inhibitors in
preclinical through Phase II testing for a range of solid tumors including
BRAF-mutant melanoma (see The next battle line against melanoma, page 4).
Published online Jan. 9, 2014
Patent pending for an assay
to identify tumors with activating mutations in AKT; licensing status
Shi, H. et al. Cancer
Discov.; published online Nov. 21, 2013;
Shi, H. et al. Cancer Discov.; published online Nov. 21, 2013;
Contact: Roger S. Lo, University of California, Los Angeles,
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