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Ref Type Journal Article
PMID (25560806)
Authors Teng PN, Bateman NW, Darcy KM, Hamilton CA, Maxwell GL, Bakkenist CJ, Conrads TP
Title Pharmacologic inhibition of ATR and ATM offers clinically important distinctions to enhancing platinum or radiation response in ovarian, endometrial, and cervical cancer cells.
Journal Gynecologic oncology
Vol 136
Issue 3
Date 2015 Mar
URL
Abstract Text Significant reductions in gynecologic (GYN) cancer mortality and morbidity require treatments that prevent and reverse resistance to chemotherapy and radiation. The objective of this study was to determine if pharmacologic inhibition of key DNA damage response kinases in GYN cancers would enhance cell killing by platinum-based chemotherapy and radiation.A panel of human ovarian, endometrial and cervical cancer cell lines were treated with platinum drugs or ionizing radiation (IR) along with small molecule pharmacological kinase inhibitors of Ataxia telangiectasia mutated (ATM) and ATM and Rad-3-related (ATR).Pharmacologic inhibition of ATR significantly enhanced platinum drug response in all GYN cancer cell lines tested, whereas inhibition of ATM did not enhance the response to platinum drugs. Co-inhibition of ATM and ATR did not enhance platinum kill beyond that observed by inhibition of ATR alone. By contrast, inhibiting either ATR or ATM enhanced the response to IR in all GYN cancer cells, with further enhancement achieved with co-inhibition.These studies highlight actionable mechanisms operative in GYN cancer cells with potential to maximize response of platinum agents and radiation in newly diagnosed as well as recurrent gynecologic cancers.

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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
ETP-46464 ETP-46464 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
ETP-46464 ATR Inhibitor 10 ETP-46464 inhibits ATR, potentially resulting in increased tumor cell sensitivity to other anti-cancer agents (PMID: 25560806, PMID: 21552262).
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
Unknown unknown cervical cancer not applicable ETP-46464 + Radiotherapy Preclinical - Cell culture Actionable In a preclinical study, ETP-46464 increased the sensitivity of cervical cancer cell lines to ionizing radiation in culture (PMID: 25560806). 25560806
Unknown unknown ovarian cancer not applicable ETP-46464 + Radiotherapy Preclinical - Cell culture Actionable In a preclinical study, ETP-46464 increased the sensitivity of ovarian cancer cell lines to ionizing radiation in culture (PMID: 25560806). 25560806
Unknown unknown ovarian cancer not applicable Cisplatin + VE-821 Preclinical - Cell culture Actionable In a preclinical study, VE-821 increased the sensitivity of an ovarian cancer cell line to Platinol (cisplatin) in culture (PMID: 25560806). 25560806
Unknown unknown endometrial cancer not applicable Cisplatin + VE-821 Preclinical - Cell culture Actionable In a preclinical study, VE-821 increased the sensitivity of an endometrial cancer cell line to Platinol (cisplatin) in culture (PMID: 25560806). 25560806
Unknown unknown cervical cancer not applicable Cisplatin + ETP-46464 Preclinical - Cell culture Actionable In a preclinical study, ETP-46464 increased the sensitivity of cervical cancer cell lines to Platinol (cisplatin) in culture (PMID: 25560806). 25560806
Unknown unknown ovarian cancer not applicable Cisplatin + ETP-46464 Preclinical - Cell culture Actionable In a preclinical study, ETP-46464 increased the sensitivity of ovarian cancer cell lines to Platinol (cisplatin) in culture (PMID: 25560806). 25560806
Unknown unknown endometrial cancer not applicable Cisplatin + ETP-46464 Preclinical - Cell culture Actionable In a preclinical study, ETP-46464 increased the sensitivity of endometrial cancer cell lines to Platinol (cisplatin) in culture (PMID: 25560806). 25560806
Unknown unknown endometrial cancer not applicable ETP-46464 + Radiotherapy Preclinical - Cell culture Actionable In a preclinical study, ETP-46464 increased the sensitivity of endometrial cancer cell lines to ionizing radiation in culture (PMID: 25560806). 25560806
Unknown unknown ovarian cancer not applicable Carboplatin + ETP-46464 Preclinical - Cell culture Actionable In a preclinical study, ETP-46464 increased the sensitivity of ovarian cancer cell lines to Paraplatin (carboplatin) in culture (PMID: 25560806). 25560806
Unknown unknown cervical cancer not applicable Cisplatin + VE-821 Preclinical - Cell culture Actionable In a preclinical study, VE-821 increased the sensitivity of a cervical cancer cell line to Platinol (cisplatin) in culture (PMID: 25560806). 25560806