{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T13:37:27Z","timestamp":1790429847555,"version":"4.1.0"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T00:00:00Z","timestamp":1645142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Replication protein A (RPA) plays essential roles in DNA replication, repair, recombination, and the DNA damage response (DDR). Retrospective analysis of lung cancer patient data demonstrates high RPA expression as a negative prognostic biomarker for overall survival in smoking-related lung cancers. Similarly, relative expression of RPA is a predictive marker for response to chemotherapy. These observations are consistent with the increase in RPA expression serving as an adaptive mechanism that allows tolerance of the genotoxic stress resulting from carcinogen exposure. We have developed second-generation RPA inhibitors (RPAis) that block the RPA\u2013DNA interaction and optimized formulation for <jats:italic>in vivo<\/jats:italic> analyses. Data demonstrate that unlike first-generation RPAis, second-generation molecules show increased cellular permeability and induce cell death <jats:italic>via<\/jats:italic> apoptosis. Second-generation RPAis elicit single-agent <jats:italic>in vitro<\/jats:italic> anticancer activity across a broad spectrum of cancers, and the cellular response suggests existence of a threshold before chemical RPA exhaustion induces cell death. Chemical RPA inhibition potentiates the anticancer activity of a series of DDR inhibitors and traditional DNA-damaging cancer therapeutics. Consistent with chemical RPA exhaustion, we demonstrate that the effects of RPAi on replication fork dynamics are similar to other known DDR inhibitors. An optimized formulation of RPAi NERx <jats:bold>329<\/jats:bold> was developed that resulted in single-agent anticancer activity in two non-small cell lung cancer models. These data demonstrate a unique mechanism of action of RPAis eliciting a state of chemical RPA exhaustion and suggest they will provide an effective therapeutic option for difficult-to-treat lung cancers.<\/jats:p>","DOI":"10.3389\/fonc.2022.826655","type":"journal-article","created":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T10:28:29Z","timestamp":1645180109000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":25,"title":["In Vivo Targeting Replication Protein A for Cancer Therapy"],"prefix":"10.3389","volume":"12","author":[{"given":"Pamela S.","family":"VanderVere-Carozza","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Navnath S.","family":"Gavande","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shadia I.","family":"Jalal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen E.","family":"Pollok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elmira","family":"Ekinci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Heyza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve M.","family":"Patrick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andi","family":"Masters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"Turchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine S.","family":"Pawelczak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-050913-022545","article-title":"Synthetic Lethality and Cancer Therapy: Lessons Learned From the Development of PARP Inhibitors","volume":"66","author":"Lord","year":"2015","journal-title":"Annu Rev Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-021-00386-6","article-title":"Targeting the DNA Damage Response in Immuno-Oncology: Developments and Opportunities","volume":"21","author":"Chabanon","year":"2021","journal-title":"Nat Rev Cancer"},{"key":"B3","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.pharmthera.2016.02.003","article-title":"DNA Repair Targeted Therapy: The Past or Future of Cancer Treatment","volume":"160","author":"Gavande","year":"2016","journal-title":"Pharmacol Ther"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.10.043","article-title":"ATR Prohibits Replication Catastrophe by Preventing Global Exhaustion of RPA","volume":"155","author":"Toledo","year":"2013","journal-title":"Cell"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.05.001","article-title":"Replication Catastrophe: When a Checkpoint Fails Because of Exhaustion","volume":"66","author":"Toledo","year":"2017","journal-title":"Mol Cell"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-3422","article-title":"Targeted Inhibition of Replication Protein A Reveals Cytotoxic Activity, Synergy With Chemotherapeutic DNA-Damaging Agents, and Insight Into Cellular Function","volume":"70","author":"Shuck","year":"2010","journal-title":"Cancer Res"},{"key":"B7","doi-asserted-by":"publisher","first-page":"304035","DOI":"10.4061\/2010\/304035","article-title":"Targeting the OB-Folds of Replication Protein A With Small Molecules","volume":"2010","author":"Anciano Granadillo","year":"2010","journal-title":"J Nucleic Acids"},{"key":"B8","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.bcp.2014.10.013","article-title":"Chemical Inhibitor Targeting the Replication Protein A-DNA Interaction Increases the Efficacy of Pt-Based Chemotherapy in Lung and Ovarian Cancer","volume":"93","author":"Mishra","year":"2015","journal-title":"Biochem Pharmacol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.9b00440","article-title":"Structure-Guided Optimization of Replication Protein A (RPA)-DNA Interaction Inhibitors","volume":"11","author":"Gavande","year":"2020","journal-title":"ACS Med Chem Lett"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa934","article-title":"Discovery and Development of Novel DNA-PK Inhibitors by Targeting the Unique Ku-DNA Interaction","volume":"48","author":"Gavande","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2016.04.019","article-title":"The DNA Fibre Technique - 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