Reference Detail

Ref Type

Journal Article

PMID

(23274910)

Authors

He L, Torres-Lockhart K, Forster N, Ramakrishnan S, Greninger P, Garnett MJ, McDermott U, Rothenberg SM, Benes CH, Ellisen LW

Title

Mcl-1 and FBW7 control a dominant survival pathway underlying HDAC and Bcl-2 inhibitor synergy in squamous cell carcinoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	3	3	2013 Mar	324-37	Cancer Discov

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach
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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FBXW7 inact mut	Advanced Solid Tumor	sensitive	Entinostat	Preclinical	Actionable	In a preclinical study, entinostat (MS-275) inhibited cancer cells from advanced solid tumors and hematological cells harboring FBXW7 inactivating mutations in culture (PMID: 23274910).	23274910
FBXW7 inact mut	Advanced Solid Tumor	sensitive	REC-2282	Preclinical	Actionable	In a preclinical study, REC-2282 (AR-42) inhibited human cancer cell lines harboring FBXW7 inactivating mutations in culture (PMID: 23274910).	23274910
FBXW7 inact mut	Advanced Solid Tumor	sensitive	Belinostat	Preclinical	Actionable	In a preclinical study, Beleodaq (belinostat) inhibited human cancer cell lines harboring FBXW7 inactivating mutations in culture (PMID: 23274910).	23274910
FBXW7 inact mut	hematologic cancer	sensitive	REC-2282	Preclinical	Actionable	In a preclinical study, REC-2282 (AR-42) inhibited human hematologic cancer cell lines harboring FBXW7 inactivating mutations in culture (PMID: 23274910).	23274910
FBXW7 inact mut	hematologic cancer	sensitive	Entinostat	Preclinical	Actionable	In a preclinical study, entinostat (MS-275) inhibited cancer cells from advanced solid tumors and hematological cells harboring FBXW7 inactivating mutations in culture (PMID: 23274910).	23274910
FBXW7 inact mut	hematologic cancer	sensitive	Belinostat	Preclinical	Actionable	In a preclinical study, Beleodaq (belinostat) inhibited human hematologic cancer cell lines harboring FBXW7 inactivating mutations in culture (PMID: 23274910).	23274910
FBXW7 inact mut	Advanced Solid Tumor	resistant	Docetaxel	Preclinical	Actionable	In a preclinical study, human cancer cell lines harboring FBXW7 inactivating mutations were resistant to docetaxel in culture (PMID: 23274910).	23274910
FBXW7 R505C	head and neck squamous cell carcinoma	sensitive	Vorinostat	Preclinical	Actionable	In a preclinical study, Zolinza (vorinostat) inhibited growth of a head and neck squamous cell carcinoma cell line harboring FBXW7 R505C in culture (PMID: 23274910).	23274910

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