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Ribosomal protein S6 kinase (RSK) phosphorylation to predict response to BRAF, MEK or phosphoinositide 3-kinase (PI3K) inhibitors

Studies in patient samples, cell culture and mice suggest RSK phosphorylation status could predict response to BRAF, MEK or PI3K inhibitors. In a panel of cancer cell lines, reduction of RSK phosphorylation after treatment with a MEK or BRAF inhibitor was a stronger predictor of sensitivity to treatment than previously reported predictive markers, including PTEN (MMAC1; TEP1) loss or protein kinase B (PKB; PKBA; AKT; AKT1) phosphorylation. In a patient treated with both a MEK and BRAF inhibitor, RSK phosphorylation was eliminated prior to a complete response, and subsequent tumor recurrence was associated with restoration of RSK phosphorylation. In mouse xenograft models, tumors resistant to a phosphatidylinositol 3-kinase catalytic subunit a-polypeptide (PIK3CA; p110a) inhibitor had higher levels of RSK phosphorylation than sensitive tumors. In these models, adding an mammalian target of rapamycin (mTOR; FRAP; RAFT1) inhibitor decreased RSK phosphorylation and tumor growth compared with adding vehicle. Ongoing work includes clinical trials combining mTOR inhibitors with PI3K, RAF or MEK inhibitors.

SciBX 6(34); doi:10.1038/scibx.2013.946
Published online Sept. 5, 2013

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Corcoran, R.B. et al. Sci. Transl. Med.; published online July 31, 2013;
Contact: Jeffrey A. Engelman, Massachusetts General Hospital Cancer Center, Boston, Mass.
Contact: Daniel A. Haber,
same affiliation as above

Elkabets, M. et al. Sci. Transl. Med.; published online July 31, 2013;
Contact: José Baselga, Memorial Sloan-Kettering Cancer Center,
New York, N.Y.
Contact: Maurizio Scaltriti,
same affiliation as above