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

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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	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	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 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
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 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	Belinostat	Preclinical	Actionable	In a preclinical study, Beleodaq (belinostat) inhibited human cancer cell lines harboring FBXW7 inactivating mutations in culture (PMID: 23274910).	23274910