Reference Detail

Ref Type

Journal Article

PMID

(28224663)

Authors

Hinrichsen I, Ackermann A, Düding T, Graband A, Filmann N, Plotz G, Zeuzem S, Brieger A

Title

Loss of MLH1 sensitizes colon cancer cells to DNA-PKcs inhibitor KU60648.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular carcinogenesis	56	7	2017 Jul	1816-1824	Mol Carcinog

URL

Abstract Text

Germline mutations of MLH1 are responsible for tumor generation in nearly 50% of patients with Lynch Syndrome, and around 15% of sporadic colorectal cancers show MLH1-deficiency due to promotor hypermethylation. Although these tumors are of lower aggressiveness the benefit for these patients from standard chemotherapy is still under discussion. Recently, it was shown that the sensitivity to the DNA-PKcs inhibitor KU60648 is linked to loss of the MMR protein MSH3. However, loss of MSH3 is rather secondary, as a consequence of MMR-deficiency, and frequently detectable in MLH1-deficient tumors. Therefore, we examined the expression of MLH1, MSH2, MSH6, and MSH3 in different MMR-deficient and proficient cell lines and determined their sensitivity to KU60648 by analyzing cell viability and survival. MLH1-dependent ability of double strand break (DSB) repair was monitored after irradiation via γH2AX detection. A panel of 12 colon cancer cell lines, two pairs of cells, where MLH1 knock down was compared to controls with the same genetic background, and one MLH1-deficient cell line where MLH1 was overexpressed, were included. In summary, we found that MLH1 and/or MSH3-deficient cells exhibited a significantly higher sensitivity to KU60648 than MMR-proficient cells and that overexpression of MLH1 in MLH1-deficient cells resulted in a decrease of cell sensitivity. KU60648 efficiency seems to be associated with reduced DSB repair capacity. Since the molecular testing of colon tumors for MLH1 expression is a clinical standard we believe that MLH1 is a much better marker and a greater number of patients would benefit from KU60648 treatment.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
MLH1	NCBI	COCA2\|FCC2\|hMLH1\|HNPCC\|HNPCC2\|LYNCH2\|MLH-1\|MMRCS1		MLH1, mutL homolog 1, is a tumor suppressor (PMID: 30562755) that dimerizes with Pms2 to form a component of the DNA mismatch repair (MMR) system (PMID: 16873062), and is associated with microsatellite instability (MSI) (PMID: 30121009) and genomic stability (PMID: 31747945). MLH1 promoter hypermethylation, resulting in Mlh1 deficiency, is frequently associated with sporadic colorectal, gastric, and esophageal cancers (PMID: 23555617, PMID: 21988782, PMID: 28224663, PMID: 28454461), and germline MLH1 mutations are associated with Lynch (Hereditary Nonpolyposis Colorectal Cancer) syndrome (PMID: 15528792).	Tumor suppressor

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
KU60648	KU60648	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
KU60648		KU-0060648	DNA_PK Inhibitor 9	KU60648 is a DNA protein kinase inhibitor, which may lead to impairment of double stranded break repair, thereby resulting in decreased cell viability (PMID: 28224663).

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
MLH1 loss	colon cancer	sensitive	KU60648	Preclinical - Cell culture	Actionable	In a preclinical study, MLH1 deficient colon cancer cell lines were sensitive to KU60648 in culture, demonstrating decreased cell viability and reduced colony formation (PMID: 28224663).	28224663
MSH6 loss	colon cancer	no benefit	KU60648	Preclinical - Cell culture	Actionable	In a preclinical study, MSH6 deficient colon cancer cells did not respond to treatment with KU60648 in culture (PMID: 28224663).	28224663