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

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 in vivo. Moreover, somatic FBW7 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. Significance: 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 FBW7 mutations, are those most resistant to standard chemotherapy. Cancer Discov; 3(3); 324–37.