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However, there are approximately 450 proteins involved in DDR, and a number of these other targets are being investigated in the laboratory and clinic. We review the most recent evidence for the clinical effect of PARP inhibition in breast and ovarian cancer and explore expansion into the first-line setting and into other tumor types. We critique the evidence for patient selection techniques and summarize what is known about mechanisms of PARP inhibitor resistance. We then discuss what is known about the preclinical rationale for targeting other members of the DDR pathway and the associated tumor cell genetics that may confer sensitivity to these agents. Examples include DNA damage sensors (MLH1), damage signaling molecules (ataxia-telangiectasia mutated; ataxia-telangiectasia mutated\u2013related and Rad3-related; CHK1\/2; DNA-dependent protein kinase, catalytic subunit; WEE1; CDC7), or effector proteins for repair (POLQ [also referred to as POL\u03b8], RAD51, poly [ADP-ribose] glycohydrolase). Early-phase clinical trials targeting some of these molecules, either as a single agent or in combination, are discussed. Finally, we outline the challenges that must be addressed to maximize the therapeutic opportunity that targeting DDR provides. <\/jats:p>","DOI":"10.1200\/jco.18.02050","type":"journal-article","created":{"date-parts":[[2019,5,3]],"date-time":"2019-05-03T19:59:54Z","timestamp":1556913594000},"page":"2257-2269","update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":181,"title":["Moving From Poly (ADP-Ribose) Polymerase Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy"],"prefix":"10.1200","volume":"37","author":[{"given":"Charlie","family":"Gourley","sequence":"first","affiliation":[{"name":"Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Edinburgh Centre, MRC IGMM, University of Edinburgh, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Balma\u00f1a","sequence":"additional","affiliation":[{"name":"Vall d\u2019Hebron University Hospital, Barcelona, Spain"},{"name":"Vall d\u2019Hebron Institute of Oncology, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan A.","family":"Ledermann","sequence":"additional","affiliation":[{"name":"UCL Cancer Institute University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Violeta","family":"Serra","sequence":"additional","affiliation":[{"name":"Vall d\u2019Hebron Institute of Oncology, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Dent","sequence":"additional","affiliation":[{"name":"National Cancer Center and Duke - NUS Medical School, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sibylle","family":"Loibl","sequence":"additional","affiliation":[{"name":"German Breast Group, Neu-Isenburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Pujade-Lauraine","sequence":"additional","affiliation":[{"name":"ARCAGY-GINECO, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon J.","family":"Boulton","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute, London, United Kingdom"},{"name":"Artios Pharma, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"233","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08467"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3891"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-1050"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.05.015"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2007.11.015"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2007.113"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4553"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2015.4"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2015.10.040"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1963"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-2753"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-2287"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.26.9589"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30376-X"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30469-2"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1611310"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)32440-6"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(14)70228-1"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2015.12.020"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2017.08.022"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.56.2728"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1810858"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1706450"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1802905"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/s41523-017-0052-4"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy460"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1513749"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1506859"},{"key":"B33","doi-asserted-by":"crossref","unstructured":"Abida W, Bryce AH, Vogelzang NJ, et al: Preliminary results from TRITON2: A phase 2 study of rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination repair (HRR) gene alterations. 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