Data from Mcl-1 and FBW7 Control a Dominant Survival Pathway Underlying HDAC and Bcl-2 Inhibitor Synergy in Squamous Cell Carcinoma

Abstract

<div>Abstract<p>Effective targeted therapeutics for squamous cell carcinoma (SCC) are lacking. Here, we uncover Mcl-1 as a dominant and tissue-specific survival factor in SCC, providing a roadmap for a new therapeutic approach. Treatment with the histone deacetylase (HDAC) inhibitor vorinostat regulates Bcl-2 family member expression to disable the Mcl-1 axis and thereby induce apoptosis in SCC cells. Although Mcl-1 dominance renders SCC cells resistant to the BH3-mimetic ABT-737, vorinostat primes them for sensitivity to ABT-737 by shuttling Bim from Mcl-1 to Bcl-2/Bcl-xl, resulting in dramatic synergy for this combination and sustained tumor regression <i>in vivo</i>. Moreover, somatic <i>FBW7</i> mutation in SCC is associated with stabilized Mcl-1 and high Bim levels, resulting in a poor response to standard chemotherapy but a robust response to HDAC inhibitors and enhanced synergy with the combination vorinostat/ABT-737. Collectively, our findings provide a biochemical rationale and predictive markers for the application of this therapeutic combination in SCC.</p><p><b>Significance:</b> This study reveals the tissue-specific landscape and biochemistry of the Bcl-2 family in SCC, which underlie moderate sensitivity of these tumors to HDAC inhibitor therapy but dramatic synergy in combination with BH3-mimetic therapy. By establishing predictive biomarkers, we provide evidence that tumors most likely to respond to this therapeutic combination, including those harboring somatic <i>FBW7</i> mutations, are those most resistant to standard chemotherapy. <i>Cancer Discov; 3(3); 324–37. ©2012 AACR.</i></p><p>See related commentary by Pickering and Myers, p. 258</p><p>This article is highlighted in the In This Issue feature, p. 239</p></div>