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Synchronous BRAFV600E and MEK inhibition leads to superior control of murine melanoma by limiting MEK inhibitor induced skin toxicity

Authors Gadiot J, Hooijkaas AI, Deken MA, Blank CU

Received 6 August 2013

Accepted for publication 21 September 2013

Published 28 November 2013 Volume 2013:6 Pages 1649—1658


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 4

Jules Gadiot,1,* Anna I Hooijkaas,1,* Marcel A Deken,1 Christian U Blank1,2

1Department of Immunology, 2Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands

* These authors contributed equally to this work

Abstract: The BRAF inhibitor (BRAFi) treatment has led to impressive responses in BRAFV600E mutation-positive melanomas, but responses are not durable in many patients. As most of the BRAFi escape mechanisms involve ERK reactivation, combinations with MEK inhibitors (MEKi) are currently tested to improve BRAFi-mediated response durations. Additionally, such a combination is expected to reduce MEKi-induced skin toxicities, as these drugs are thought to have antagonistic effects on ERK activation in keratinocytes. However, preclinical in vivo data exploring the combination of BRAFi and MEKi to achieve improved tumor control in the absence of skin toxicities are limited. Using a murine Tyr::CreERT2;PtenLoxP/LoxP;BrafCA/+ melanoma model, we have determined the effect of BRAFi and MEKi treatment and their combination on melanoma control and occurrence of adverse events. We found that the MEKi dosed beyond the maximum tolerable dose (MTD) led to stronger control of tumor growth than did the BRAFi, but mice had to be removed from treatment because of skin toxicity. The combination of BRAFi and MEKi reduced MEKi-associated skin toxicity. This allowed high and long-term dosing of the MEKi, resulting in long-term tumor control. In contrast to previous hypotheses, the addition of a BRAFi did not restore the MEKi-mediated downregulation of pErk1/2 in skin cells. Our data describe, for the first time, the alleviation of MEKi-mediated dose-limiting toxicity by addition of a BRAFi in a mouse melanoma model. Additional clinical Phase I studies should be implemented to explore MEKi dosing beyond the single drug MTD in combination with BRAFi.

Keywords: melanoma, BRAF, MEK, skin toxicity, vemurafenib, trametinib

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