Abstract:
: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.
journal_name
Cancer Discovjournal_title
Cancer discoveryauthors
He L,Torres-Lockhart K,Forster N,Ramakrishnan S,Greninger P,Garnett MJ,McDermott U,Rothenberg SM,Benes CH,Ellisen LWdoi
10.1158/2159-8290.CD-12-0417subject
Has Abstractpub_date
2013-03-01 00:00:00pages
324-37issue
3eissn
2159-8274issn
2159-8290pii
2159-8290.CD-12-0417journal_volume
3pub_type
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