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 Molecular cancer research : MCR
Vol 13
Issue 10
Date 2015 Oct
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 4 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
YU238259 YU238259 is a sulfonamide compound that inhibits homology-dependent DSB repair, therefore sensitizing tumor cells to DSB-inducing treatments (PMID: 26116172).
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
BRCA2 loss colorectal cancer sensitive Etoposide + YU238259 Preclinical Actionable In a preclinical study, YU238259 and Eposin (etoposide) synergistically inhibited survival of colorectal cancer cell lines harboring BRCA2 loss in culture (PMID: 26116172). 26116172
BRCA2 loss colorectal cancer sensitive Radiotherapy + YU238259 Preclinical Actionable In a preclinical study, YU238259 and radiotherapy synergistically inhibited survival of colorectal cancer cell lines harboring BRCA2 loss in culture (PMID: 26116172). 26116172
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
BRCA2 loss ovary adenocarcinoma sensitive YU238259 Preclinical Actionable In a preclinical study, YU238259 demonstrated increased cytotoxicity compared to control in BRCA2-deficient ovarian adenocarcinoma 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
BRCA2 loss colorectal cancer sensitive Olaparib + YU238259 Preclinical - Cell culture Actionable In a preclinical study, YU238259 and Lynparza (olaparib) synergistically inhibited survival of colorectal cancer cell lines harboring BRCA2 loss in culture (PMID: 26116172). 26116172
BRCA2 loss colorectal cancer sensitive YU238259 Preclinical - Cell line xenograft Actionable In a preclinical study, YU238259 induced cytotoxicity in a human BRCA2-deficient colorectal cancer cell line in culture and slowed tumor growth in xenograft models (PMID: 26116172). 26116172