Reference Detail

Ref Type

Journal Article

PMID

(27262172)

Authors

Zhang Y, Fox JT, Park YU, Elliott G, Rai G, Cai M, Sakamuru S, Huang R, Xia M, Lee K, Jeon MH, Mathew BP, Park HD, Edelmann W, Park CY, Hong SY, Maloney D, Myung K

Title

A Novel Chemotherapeutic Agent to Treat Tumors with DNA Mismatch Repair Deficiencies.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	76	14	2016 Jul 15	4183-91	Cancer Res

URL

Abstract Text

Impairing the division of cancer cells with genotoxic small molecules has been a primary goal to develop chemotherapeutic agents. However, DNA mismatch repair (MMR)-deficient cancer cells are resistant to most conventional chemotherapeutic agents. Here we have identified baicalein as a small molecule that selectively kills MutSα-deficient cancer cells. Baicalein binds preferentially to mismatched DNA and induces a DNA damage response in a MMR-dependent manner. In MutSα-proficient cells, baicalein binds to MutSα to dissociate CHK2 from MutSα leading to S-phase arrest and cell survival. In contrast, continued replication in the presence of baicalein in MutSα-deficient cells results in a high number of DNA double-strand breaks and ultimately leads to apoptosis. Consistently, baicalein specifically shrinks MutSα-deficient xenograft tumors and inhibits the growth of AOM-DSS-induced colon tumors in colon-specific MSH2 knockout mice. Collectively, baicalein offers the potential of an improved treatment option for patients with tumors with a DNA MMR deficiency. Cancer Res; 76(14); 4183-91. ©2016 AACR.

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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
Baicalein	Baicalein	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Baicalein				Baicalein is a plant-derived small molecule that binds to Msh2 and mismatched DNA and inhibits the interaction between Msh2 and Chk1/Atm, resulting in increased double-strand breaks and cell death in mismatch repair-deficient tumor cells (PMID: 27262172), and induces DDIT4 expression, which leads to inhibition of mTORC1 activity (PMID: 25543165, PMID: 32800561).

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
MSH2 inact mut	endometrial adenocarcinoma	sensitive	Baicalein	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Baicalein selectively induced cell death in an endometrial adenocarcinoma cell line with MSH2 inactivation in culture, and induced apoptosis and tumor shrinkage in MSH2-deficient endometrial adenocarcinoma cell line xenograft models (PMID: 27262172).	27262172
MSH2 inact mut	colon cancer	sensitive	Baicalein	Preclinical	Actionable	In a preclinical study, treatment with Baicalein resulted in decreased growth of azoxymethane/dextran sodium sulfate-induced colon tumors in a MSH2-deficient mouse model (PMID: 27262172).	27262172