Reference Detail

Ref Type

Journal Article

PMID

(26116172)

Authors

Stachelek GC, Peterson-Roth E, Liu Y, Fernandez RJ, Pike LR, Qian JM, Abriola L, Hoyer D, Hungerford W, Merkel J, Glazer PM

Title

YU238259 Is a Novel Inhibitor of Homology-Dependent DNA Repair That Exhibits Synthetic Lethality and Radiosensitization in Repair-Deficient Tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer research : MCR	13	10	2015 Oct	1389-97	Mol Cancer Res

URL

Abstract Text

Radiotherapy and DNA-damaging chemotherapy are frequently utilized in the treatment of solid tumors. Innate or acquired resistance to these therapies remains a major clinical challenge in oncology. The development of small molecules that sensitize cancers to established therapies represents an attractive approach to extending survival and quality of life in patients. Here, we demonstrate that YU238259, a member of a novel class of DNA double-strand break repair inhibitors, exhibits potent synthetic lethality in the setting of DNA damage response and DNA repair defects. YU238259 specifically inhibits homology-dependent DNA repair, but not non-homologous end-joining, in cell-based GFP reporter assays. Treatment with YU238259 is not only synergistic with ionizing radiation, etoposide, and PARP inhibition, but this synergism is heightened by BRCA2 deficiency. Further, growth of BRCA2-deficient human tumor xenografts in nude mice is significantly delayed by YU238259 treatment even in the absence of concomitant DNA-damaging therapy. The cytotoxicity of these small molecules in repair-deficient cells results from an accumulation of unresolved DNA double-strand breaks. These findings suggest that YU238259 or related small molecules may have clinical benefit to patients with advanced BRCA2-negative tumors, either as a monotherapy or as an adjuvant to radiotherapy and certain chemotherapies.We have identified a novel series of compounds that demonstrate synthetic lethality in DNA repair-deficient cell and animal models and have strong potential for clinical translation.

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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
YU238259	YU238259	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
YU238259		YU-238259		YU238259 is a sulfonamide compound that inhibits homology-dependent DSB repair, therefore sensitizing tumor cells to DSB-inducing treatments (PMID: 26116172).

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
ATM loss	Advanced Solid Tumor	sensitive	YU238259	Preclinical	Actionable	In a preclinical study, YU238259 demonstrated increased cytotoxicity in ATM-deficient transformed human cell lines in culture (PMID: 26116172).	26116172
PTEN loss	sarcoma	sensitive	YU238259	Preclinical	Actionable	In a preclinical study, YU238259 demonstrated increased cytotoxicity in PTEN-deficient sarcoma cell lines in culture (PMID: 26116172).	26116172