The efficacy of MEK-inhibitor treatment of B-Raf mutant tumours requires Bim and is enhanced by the BH3-mimetic ABT-737


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Mark Cragg1, Elisa Jansen2, Michelle Cook2, Claire Harris1, Andreas Strasser2, Clare Scott2

1Southampton University School of Medicine, UK, 2Walter and Eliza Hall Institute, Melbourne, Australia

Abstract

B-Raf is frequently mutated in solid tumours, resulting in activation of the MEK/ERK signaling pathway. MEK inhibition in these cells results predominantly in cell cycle arrest and cytostasis. We analysed B-raf mutant tumours to determine ways of improving cancer cell death, with the aim of improving therapeutic efficacy. We showed that apoptosis was triggered by MEK inhibition and was dependent on up-regulation and de-phosphorylation of the pro-apoptotic BH3-only Bcl-2 family member, Bim. However, up-regulation of Bim was insufficient for extensive apoptosis and was countered by Bcl-2 over-expression.

To overcome apoptotic resistance, we treated B-Raf mutant cells with the combination of MEK inhibitors and the BH3-mimetic ABT-737, resulting in profound synergism, due to efficient antagonism of Mcl-1 by Bim and inhibition of Bcl-2 and Bcl-xL by ABT-737. Critically, addition of ABT-737 converted the predominantly cytostatic effect of MEK inhibition to a cytotoxic effect, causing long-term tumour regression in human tumour xenograft models. Using studies with tumour cells addicted to three different oncogenic kinases, BCR-ABL, mutated EGF-R and now mutated B-Raf, we have demonstrated that their efficient killing by specific kinase inhibitors requires up-regulation and de-phosphorylation of Bim but can be blocked by high levels of Bcl-2. Thus, therapeutic efficacy of inhibitors of the MEK/ERK pathway often requires concurrent unleashing of apoptosis by a BH3 mimetic.

The accurate identification of the Achilles heel of individual cancers and subsequent design of appropriate targeted combination therapy including a powerful apoptotic response represents a potent novel approach for solid tumours.