{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T19:29:31Z","timestamp":1793647771461,"version":"4.5.1"},"reference-count":104,"publisher":"Elsevier BV","issue":"5","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"US Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-22-2-0025"],"award-info":[{"award-number":["W81XWH-22-2-0025"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010711","name":"Sy\u00f6p\u00e4s\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007249","name":"University of Minnesota","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007249","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["K12GM000678"],"award-info":[{"award-number":["K12GM000678"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004070","name":"Khalifa University of Science, Technology and Research","doi-asserted-by":"publisher","award":["FSU-2025-022"],"award-info":[{"award-number":["FSU-2025-022"]}],"id":[{"id":"10.13039\/501100004070","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"National Institute of Allergy and Infectious Diseases Division of Intramural Research","doi-asserted-by":"publisher","award":["4R00AI175656-03"],"award-info":[{"award-number":["4R00AI175656-03"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007316","name":"National Cancer Institute Division of Cancer Prevention","doi-asserted-by":"publisher","award":["R01CA279968"],"award-info":[{"award-number":["R01CA279968"]}],"id":[{"id":"10.13039\/100007316","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007316","name":"National Cancer Institute Division of Cancer Prevention","doi-asserted-by":"publisher","award":["R01CA204856"],"award-info":[{"award-number":["R01CA204856"]}],"id":[{"id":"10.13039\/100007316","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007316","name":"National Cancer Institute Division of Cancer Prevention","doi-asserted-by":"publisher","award":["P30 CA077598"],"award-info":[{"award-number":["P30 CA077598"]}],"id":[{"id":"10.13039\/100007316","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007316","name":"National Cancer Institute Division of Cancer Prevention","doi-asserted-by":"publisher","award":["R01CA229618"],"award-info":[{"award-number":["R01CA229618"]}],"id":[{"id":"10.13039\/100007316","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["cell.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Med"],"published-print":{"date-parts":[[2026,5]]},"DOI":"10.1016\/j.medj.2026.101103","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T03:31:47Z","timestamp":1777606307000},"page":"101103","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":2,"title":["Rethinking the role of synergy calculations in the next century of drug combination discovery"],"prefix":"10.1016","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8719-6522","authenticated-orcid":false,"given":"Christian T.","family":"Meyer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunxing","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy E.","family":"Pomeroy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel R.","family":"Twarog","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Bender","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven S.","family":"Rosenfeld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel S.","family":"Antonarakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerome T.","family":"Mettetal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Stephanie","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vito","family":"Quaranta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anang A.","family":"Shelat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malcolm A.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam C.","family":"Palmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.medj.2026.101103_bib1","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/BF01952257","article-title":"\u00fcber Kombination swirkungen","volume":"114","author":"Loewe","year":"1926","journal-title":"Arch fur Exp Pathol."},{"key":"10.1016\/j.medj.2026.101103_bib2","first-page":"1","article-title":"Advances in chemotherapy of cancer in man","volume":"4","author":"Farber","year":"1956","journal-title":"Adv. Cancer Res."},{"key":"10.1016\/j.medj.2026.101103_bib3","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1056\/NEJMra1400972","article-title":"Acute Lymphoblastic Leukemia in Children","volume":"373","author":"Hunger","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.medj.2026.101103_bib4","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1002\/1097-0142(197501)35:1<25::AID-CNCR2820350105>3.0.CO;2-S","article-title":"Combined modality therapy of acute lymphocytic leukemia","volume":"35","author":"Simone","year":"1975","journal-title":"Cancer"},{"key":"10.1016\/j.medj.2026.101103_bib5","doi-asserted-by":"crossref","DOI":"10.1002\/pbc.29256","article-title":"Late isolated central nervous system relapse in childhood B-cell acute lymphoblastic leukemia treated with intensified systemic therapy and delayed reduced dose cranial radiation: A report from the Children's Oncology Group study AALL02P2","volume":"68","author":"Hastings","year":"2021","journal-title":"Pediatr. Blood Cancer"},{"key":"10.1016\/j.medj.2026.101103_bib6","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1182\/blood.V26.5.642.642","article-title":"The effectiveness of combinations of antileukemic agents in inducing and maintaining remission in children with acute leukemia","volume":"26","author":"Frei","year":"1965","journal-title":"Blood"},{"key":"10.1016\/j.medj.2026.101103_bib7","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1016\/j.trecan.2022.06.009","article-title":"Drug independence and the curability of cancer by combination chemotherapy","volume":"8","author":"Pomeroy","year":"2022","journal-title":"Trends Cancer"},{"key":"10.1016\/j.medj.2026.101103_bib8","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1056\/NEJMoa2411680","article-title":"Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children","volume":"392","author":"Gupta","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.medj.2026.101103_bib9","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1038\/s43018-023-00667-z","article-title":"Additivity predicts the efficacy of most approved combination therapies for advanced cancer","volume":"4","author":"Hwangbo","year":"2023","journal-title":"Nat. Cancer"},{"key":"10.1016\/j.medj.2026.101103_bib10","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/978-1-4939-9089-4_2","article-title":"High-Throughput Screening for Drug Combinations","volume":"1939","author":"Shinn","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"10.1016\/j.medj.2026.101103_bib11","doi-asserted-by":"crossref","DOI":"10.1016\/j.xpro.2024.103354","article-title":"Protocol to calculate the synergy of drug combinations in organoids and primary cells from murine tumors","volume":"5","author":"Eisenbarth","year":"2024","journal-title":"STAR Protoc."},{"key":"10.1016\/j.medj.2026.101103_bib12","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2023.112324","article-title":"Drug-repurposing screen on patient-derived organoids identifies therapy-induced vulnerability in KRAS-mutant colon cancer","volume":"42","author":"Mertens","year":"2023","journal-title":"Cell Rep."},{"key":"10.1016\/j.medj.2026.101103_bib13","article-title":"AI-driven discovery of synergistic drug combinations against pancreatic cancer","author":"Pourmousa","year":"2024","journal-title":"ChemRxiv"},{"key":"10.1016\/j.medj.2026.101103_bib14","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.tips.2020.01.011","article-title":"Charting the Fragmented Landscape of Drug Synergy","volume":"41","author":"Meyer","year":"2020","journal-title":"Trends Pharmacol. Sci."},{"key":"10.1016\/j.medj.2026.101103_bib15","doi-asserted-by":"crossref","first-page":"2286","DOI":"10.1016\/j.drudis.2019.09.002","article-title":"Applying synergy metrics to combination screening data: agreements, disagreements and pitfalls","volume":"24","author":"Vlot","year":"2019","journal-title":"Drug Discov. Today"},{"key":"10.1016\/j.medj.2026.101103_bib16","first-page":"65","article-title":"Consensus on Concepts and Terminology for Combined-action Assessment: The Saariselka Agreement","volume":"4","author":"Greco","year":"1992","journal-title":"Arch. Complex Environ. Stud."},{"key":"10.1016\/j.medj.2026.101103_bib17","doi-asserted-by":"crossref","first-page":"4607","DOI":"10.1038\/s41467-021-24789-z","article-title":"MuSyC is a consensus framework that unifies multi-drug synergy metrics for combinatorial drug discovery","volume":"12","author":"Wooten","year":"2021","journal-title":"Nat. Commun."},{"key":"10.1016\/j.medj.2026.101103_bib18","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0031-6997(25)06847-4","article-title":"The search for synergy: a critical review from a response surface perspective","volume":"47","author":"Greco","year":"1995","journal-title":"Pharmacol. Rev."},{"key":"10.1016\/j.medj.2026.101103_bib19","doi-asserted-by":"crossref","first-page":"181","DOI":"10.3389\/fphar.2015.00181","article-title":"What is synergy? The Saariselk\u00e4 agreement revisited","volume":"6","author":"Tang","year":"2015","journal-title":"Front. Pharmacol."},{"key":"10.1016\/j.medj.2026.101103_bib20","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/B978-1-4831-9930-6.50011-3","article-title":"Progress and perspectives in the chemotherapy of acute leukemia","volume":"2","author":"Frei","year":"1965","journal-title":"Adv. Chemother."},{"key":"10.1016\/j.medj.2026.101103_bib21","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1056\/NEJM197305102881905","article-title":"The use of drugs in combination for the treatment of cancer: rationale and results","volume":"288","author":"DeVita","year":"1973","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.medj.2026.101103_bib22","first-page":"871","article-title":"Effects of combinations of antileukemic agents on an acute lymphocytic leukemia of mice","volume":"12","author":"Law","year":"1952","journal-title":"Cancer Res."},{"key":"10.1016\/j.medj.2026.101103_bib23","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.50036","article-title":"A curative combination cancer therapy achieves high fractional cell killing through low cross-resistance and drug additivity","volume":"8","author":"Palmer","year":"2019","journal-title":"eLife"},{"key":"10.1016\/j.medj.2026.101103_bib24","first-page":"2593","article-title":"Combination cancer therapy: Presidential address","volume":"32","author":"Frei","year":"1972","journal-title":"Cancer Res."},{"key":"10.1016\/j.medj.2026.101103_bib25","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1158\/1078-0432.CCR-21-2275","article-title":"Predictable Clinical Benefits without Evidence of Synergy in Trials of Combination Therapies with Immune-Checkpoint Inhibitors","volume":"28","author":"Palmer","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"10.1016\/j.medj.2026.101103_bib26","doi-asserted-by":"crossref","first-page":"1678","DOI":"10.1016\/j.cell.2017.11.009","article-title":"Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy","volume":"171","author":"Palmer","year":"2017","journal-title":"Cell"},{"key":"10.1016\/j.medj.2026.101103_bib27","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1002\/1097-0142(197501)35:1<98::AID-CNCR2820350115>3.0.CO;2-B","article-title":"Combination versus single agent chemotherapy: a review of the basis for selection of drug treatment of cancer","volume":"35","author":"DeVita","year":"1975","journal-title":"Cancer"},{"key":"10.1016\/j.medj.2026.101103_bib28","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1111\/j.1744-7348.1939.tb06990.x","article-title":"The Toxicity of Poisons Applied Jointly","volume":"26","author":"Bliss","year":"1939","journal-title":"Ann. Appl. Biol."},{"key":"10.1016\/j.medj.2026.101103_bib29","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1158\/1535-7163.MCT-15-0843","article-title":"An Unbiased Oncology Compound Screen to Identify Novel Combination Strategies","volume":"15","author":"O'Neil","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"10.1016\/j.medj.2026.101103_bib30","doi-asserted-by":"crossref","first-page":"5848","DOI":"10.1038\/s41467-020-19563-6","article-title":"Computationally predicting clinical drug combination efficacy with cancer cell line screens and independent drug action","volume":"11","author":"Ling","year":"2020","journal-title":"Nat. Commun."},{"key":"10.1016\/j.medj.2026.101103_bib31","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/s41597-022-01360-z","article-title":"CDCDB: A large and continuously updated drug combination database","volume":"9","author":"Shtar","year":"2022","journal-title":"Sci. Data"},{"key":"10.1016\/j.medj.2026.101103_bib32","doi-asserted-by":"crossref","first-page":"3564","DOI":"10.1158\/0008-5472.CAN-17-0489","article-title":"The National Cancer Institute ALMANAC: A comprehensive screening resource for the detection of anticancer drug pairs with enhanced therapeutic activity","volume":"77","author":"Holbeck","year":"2017","journal-title":"Cancer Res."},{"key":"10.1016\/j.medj.2026.101103_bib33","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1056\/NEJMoa1313984","article-title":"Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions","volume":"370","author":"Goede","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.medj.2026.101103_bib34","doi-asserted-by":"crossref","DOI":"10.1016\/j.ebiom.2020.102716","article-title":"A pharmacodynamic model of clinical synergy in multiple myeloma","volume":"54","author":"Sudalagunta","year":"2020","journal-title":"EBioMedicine"},{"key":"10.1016\/j.medj.2026.101103_bib35","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1006752","article-title":"Drug combination sensitivity scoring facilitates the discovery of synergistic and efficacious drug combinations in cancer","volume":"15","author":"Malyutina","year":"2019","journal-title":"PLoS Comput. Biol."},{"key":"10.1016\/j.medj.2026.101103_bib36","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1158\/2159-8290.CD-23-0388","article-title":"Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations","volume":"14","author":"Bashi","year":"2024","journal-title":"Cancer Discov."},{"key":"10.1016\/j.medj.2026.101103_bib37","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2408889121","article-title":"Expanded profiling of WD repeat domain 5 inhibitors reveals actionable strategies for the treatment of hematologic malignancies","volume":"121","author":"Meyer","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"10.1016\/j.medj.2026.101103_bib38","doi-asserted-by":"crossref","DOI":"10.1136\/esmoopen-2020-000871","article-title":"Evaluation of the contribution of randomised cancer clinical trials evaluating agents without documented single-agent activity","volume":"5","author":"Foster","year":"2020","journal-title":"ESMO Open"},{"key":"10.1016\/j.medj.2026.101103_bib39","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/S1470-2045(19)30274-8","article-title":"Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301\/KEYNOTE-252): a phase 3, randomised, double-blind study","volume":"20","author":"Long","year":"2019","journal-title":"Lancet Oncol."},{"key":"10.1016\/j.medj.2026.101103_bib40","article-title":"LBA2 SKYSCRAPER-06: Efficacy and safety of tiragolumab plus atezolizumab plus chemotherapy (tira + atezo + chemo) vs pembrolizumab plus chemotherapy (pembro + chemo) in patients (pts) with advanced non-squamous non-small cell lung cancer (NSq NSCLC)","volume":"24","author":"Socinski","year":"2024","journal-title":"Immunooncol. Technol."},{"key":"10.1016\/j.medj.2026.101103_bib41","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1182\/blood.2024027506","article-title":"The ENHANCE-3 study: venetoclax and azacitidine plus magrolimab or placebo for untreated AML unfit for intensive therapy","volume":"146","author":"Daver","year":"2025","journal-title":"Blood"},{"key":"10.1016\/j.medj.2026.101103_bib42","doi-asserted-by":"crossref","first-page":"4756","DOI":"10.1200\/JCO.23.00172","article-title":"Bempegaldesleukin Plus Nivolumab in Untreated Advanced Melanoma: The Open-Label, Phase III PIVOT IO 001 Trial Results","volume":"41","author":"Diab","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"10.1016\/j.medj.2026.101103_bib43","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1001\/jamainternmed.2016.6008","article-title":"Failure of Investigational Drugs in Late-Stage Clinical Development and Publication of Trial Results","volume":"176","author":"Hwang","year":"2016","journal-title":"JAMA Intern. Med."},{"key":"10.1016\/j.medj.2026.101103_bib44","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.celrep.2014.09.028","article-title":"Targeting the DNA repair pathway in Ewing sarcoma","volume":"9","author":"Stewart","year":"2014","journal-title":"Cell Rep."},{"key":"10.1016\/j.medj.2026.101103_bib45","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1158\/1078-0432.CCR-19-2000","article-title":"Restoration of Temozolomide Sensitivity by PARP Inhibitors in Mismatch Repair Deficient Glioblastoma is Independent of Base Excision Repair","volume":"26","author":"Higuchi","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"10.1016\/j.medj.2026.101103_bib46","doi-asserted-by":"crossref","first-page":"2750","DOI":"10.1158\/0008-5472.CAN-22-3646","article-title":"Temozolomide Sensitizes ARID1A-Mutated Cancers to PARP Inhibitors","volume":"83","author":"Yu","year":"2023","journal-title":"Cancer Res."},{"key":"10.1016\/j.medj.2026.101103_bib47","first-page":"2275","article-title":"PARP-1 inhibition sensitizes temozolomide-treated glioblastoma cell lines and decreases drug resistance independent of MGMT activity and PTEN proficiency","volume":"44","author":"Montaldi","year":"2020","journal-title":"Oncol. Rep."},{"key":"10.1016\/j.medj.2026.101103_bib48","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1124\/jpet.113.210146","article-title":"Rationale for poly(ADP-ribose) polymerase (PARP) inhibitors in combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic inhibition","volume":"349","author":"Murai","year":"2014","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"10.1016\/j.medj.2026.101103_bib49","doi-asserted-by":"crossref","DOI":"10.1002\/pbc.28073","article-title":"Phase 1\/2 trial of talazoparib in combination with temozolomide in children and adolescents with refractory\/recurrent solid tumors including Ewing sarcoma: A Children's Oncology Group Phase 1 Consortium study (ADVL1411)","volume":"67","author":"Schafer","year":"2020","journal-title":"Pediatr. Blood Cancer"},{"key":"10.1016\/j.medj.2026.101103_bib50","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1002\/cncr.33349","article-title":"SARC025 arms 1 and 2: A phase 1 study of the poly(ADP-ribose) polymerase inhibitor niraparib with temozolomide or irinotecan in patients with advanced Ewing sarcoma","volume":"127","author":"Chugh","year":"2021","journal-title":"Cancer"},{"key":"10.1016\/j.medj.2026.101103_bib51","doi-asserted-by":"crossref","first-page":"3663","DOI":"10.1007\/s00018-010-0491-7","article-title":"Targeting O6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy","volume":"67","author":"Kaina","year":"2010","journal-title":"Cell. Mol. Life Sci."},{"key":"10.1016\/j.medj.2026.101103_bib52","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1158\/1078-0432.CCR-04-2045","article-title":"O6-methylguanine-DNA methyltransferase, O6-benzylguanine, and resistance to clinical alkylators in pediatric primary brain tumor cell lines","volume":"11","author":"Bobola","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"10.1016\/j.medj.2026.101103_bib53","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1038\/bjc.1996.203","article-title":"O6-benzylguanine enhances the sensitivity of a glioma xenograft with low O6-alkylguanine-DNA alkyltransferase activity to temozolomide and BCNU","volume":"73","author":"Wedge","year":"1996","journal-title":"Br. J. Cancer"},{"key":"10.1016\/j.medj.2026.101103_bib54","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1007\/s10147-014-0769-0","article-title":"A Phase III study of radiation therapy (RT) and O6-benzylguanine + BCNU versus RT and BCNU alone and methylation status in newly diagnosed glioblastoma and gliosarcoma: Southwest Oncology Group (SWOG) study S0001","volume":"20","author":"Blumenthal","year":"2015","journal-title":"Int. J. Clin. Oncol."},{"key":"10.1016\/j.medj.2026.101103_bib55","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.celrep.2014.02.045","article-title":"Intrinsic resistance to MEK inhibition in KRAS mutant lung and colon cancer through transcriptional induction of ERBB3","volume":"7","author":"Sun","year":"2014","journal-title":"Cell Rep."},{"key":"10.1016\/j.medj.2026.101103_bib56","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1038\/s41416-020-0776-z","article-title":"Phase 1 study of the pan-HER inhibitor dacomitinib plus the MEK1\/2 inhibitor PD-0325901 in patients with KRAS-mutation-positive colorectal, non-small-cell lung and pancreatic cancer","volume":"122","author":"van Geel","year":"2020","journal-title":"Br. J. Cancer"},{"key":"10.1016\/j.medj.2026.101103_bib57","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1002\/onco.13631","article-title":"Phase I Study of Afatinib and Selumetinib in Patients with KRAS-Mutated Colorectal, Non-Small Cell Lung, and Pancreatic Cancer","volume":"26","author":"van Brummelen","year":"2021","journal-title":"Oncologist"},{"key":"10.1016\/j.medj.2026.101103_bib58","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1007\/s00280-020-04066-4","article-title":"Phase I study of lapatinib plus trametinib in patients with KRAS-mutant colorectal, non-small cell lung, and pancreatic cancer","volume":"85","author":"Huijberts","year":"2020","journal-title":"Cancer Chemother. Pharmacol."},{"key":"10.1016\/j.medj.2026.101103_bib59","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1038\/nm.1890","article-title":"Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers","volume":"14","author":"Engelman","year":"2008","journal-title":"Nat. Med."},{"key":"10.1016\/j.medj.2026.101103_bib60","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1158\/1078-0432.CCR-14-1901","article-title":"Antitumor activity in RAS-driven tumors by blocking AKT and MEK","volume":"21","author":"Tolcher","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"10.1016\/j.medj.2026.101103_bib61","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1001\/jamaoncol.2016.5383","article-title":"Effect of Selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in Patients With Metastatic Pancreatic Cancer After Prior Therapy: SWOG S1115 Study Randomized Clinical Trial","volume":"3","author":"Chung","year":"2017","journal-title":"JAMA Oncol."},{"key":"10.1016\/j.medj.2026.101103_bib62","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/s10637-019-00776-6","article-title":"Phase Ib study of the MEK inhibitor cobimetinib (GDC-0973) in combination with the PI3K inhibitor pictilisib (GDC-0941) in patients with advanced solid tumors","volume":"38","author":"Shapiro","year":"2020","journal-title":"Invest. New Drugs"},{"key":"10.1016\/j.medj.2026.101103_bib63","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/s10637-020-00975-6","article-title":"A phase Ib open-label dose escalation study of the safety, pharmacokinetics, and pharmacodynamics of cobimetinib (GDC-0973) and ipatasertib (GDC-0068) in patients with locally advanced or metastatic solid tumors","volume":"39","author":"Shapiro","year":"2021","journal-title":"Invest. New Drugs"},{"key":"10.1016\/j.medj.2026.101103_bib64","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s00280-014-2615-5","article-title":"Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma","volume":"75","author":"Tolcher","year":"2015","journal-title":"Cancer Chemother. Pharmacol."},{"key":"10.1016\/j.medj.2026.101103_bib65","doi-asserted-by":"crossref","DOI":"10.3390\/cancers16162914","article-title":"Computational Modeling of Drug Response Identifies Mutant-Specific Constraints for Dosing panRAF and MEK Inhibitors in Melanoma","volume":"16","author":"Goetz","year":"2024","journal-title":"Cancers (Basel)"},{"key":"10.1016\/j.medj.2026.101103_bib66","doi-asserted-by":"crossref","first-page":"2651","DOI":"10.1200\/JCO.22.02018","article-title":"Initial Evidence for the Efficacy of Naporafenib in Combination With Trametinib in -Mutant Melanoma: Results From the Expansion Arm of a Phase Ib, Open-Label Study","volume":"41","author":"de Braud","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"10.1016\/j.medj.2026.101103_bib67","doi-asserted-by":"crossref","first-page":"S465","DOI":"10.1016\/j.annonc.2023.09.1847","article-title":"661MO Anti-tumor activity of belvarafenib in combination with cobimetinib in patients with metastatic solid tumors harboring BRAF fusions or BRAF class II\/III mutation","volume":"34","author":"Kim","year":"2023","journal-title":"Ann. Oncol."},{"key":"10.1016\/j.medj.2026.101103_bib68","doi-asserted-by":"crossref","first-page":"S491","DOI":"10.1016\/j.annonc.2024.08.680","article-title":"613MO A phase I clinical trial evaluating exarafenib, a selective pan-RAF inhibitor in combination with binimetinib in NRAS-mutant (NRASMut) melanoma (Mel) & BRAF-altered solid tumors","volume":"35","author":"Cassier","year":"2024","journal-title":"Ann. Oncol."},{"key":"10.1016\/j.medj.2026.101103_bib69","doi-asserted-by":"crossref","first-page":"3583","DOI":"10.1158\/0008-5472.CAN-14-3347","article-title":"CHK1 Inhibition Synergizes with Gemcitabine Initially by Destabilizing the DNA Replication Apparatus","volume":"75","author":"Koh","year":"2015","journal-title":"Cancer Res."},{"key":"10.1016\/j.medj.2026.101103_bib70","doi-asserted-by":"crossref","first-page":"5047","DOI":"10.1158\/1078-0432.CCR-23-2005","article-title":"A Phase I Expansion Cohort Study Evaluating the Safety and Efficacy of the CHK1 Inhibitor LY2880070 with Low-dose Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma","volume":"29","author":"Huffman","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"10.1016\/j.medj.2026.101103_bib71","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1186\/s12885-017-3131-x","article-title":"A phase II study to evaluate LY2603618 in combination with gemcitabine in pancreatic cancer patients","volume":"17","author":"Laquente","year":"2017","journal-title":"BMC Cancer"},{"key":"10.1016\/j.medj.2026.101103_bib72","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1158\/1078-0432.CCR-22-3094","article-title":"A Phase Ib\/II Trial of Combined BRAF and EGFR Inhibition in BRAF V600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and Vemurafenib In Combination Trial) Study","volume":"29","author":"Tan","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"10.1016\/j.medj.2026.101103_bib73","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1158\/2159-8290.CD-11-0341","article-title":"EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib","volume":"2","author":"Corcoran","year":"2012","journal-title":"Cancer Discov."},{"key":"10.1016\/j.medj.2026.101103_bib74","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/nature10868","article-title":"Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR","volume":"483","author":"Prahallad","year":"2012","journal-title":"Nature"},{"key":"10.1016\/j.medj.2026.101103_bib75","doi-asserted-by":"crossref","first-page":"1840","DOI":"10.1093\/neuonc\/noaa104","article-title":"Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial","volume":"22","author":"Hanna","year":"2020","journal-title":"Neuro Oncol."},{"key":"10.1016\/j.medj.2026.101103_bib76","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1111\/jcpt.13349","article-title":"Haematologic toxicities with PARP inhibitors in cancer patients: an up-to-date meta-analysis of 29 randomized controlled trials","volume":"46","author":"Wang","year":"2021","journal-title":"J. Clin. Pharm. Ther."},{"key":"10.1016\/j.medj.2026.101103_bib77","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/s41573-024-01060-w","article-title":"DNA damage response inhibitors in cancer therapy: lessons from the past, current status and future implications","volume":"24","author":"Drew","year":"2025","journal-title":"Nat. Rev. Drug Discov."},{"key":"10.1016\/j.medj.2026.101103_bib78","doi-asserted-by":"crossref","DOI":"10.1177\/17588359231173183","article-title":"The role of PARP inhibitor combination therapy in ovarian cancer","volume":"15","author":"Hockings","year":"2023","journal-title":"Ther. Adv. Med. Oncol."},{"key":"10.1016\/j.medj.2026.101103_bib79","doi-asserted-by":"crossref","first-page":"10966","DOI":"10.18632\/oncotarget.14089","article-title":"Combined inhibition of Wee1 and Chk1 gives synergistic DNA damage in S-phase due to distinct regulation of CDK activity and CDC45 loading","volume":"8","author":"Hauge","year":"2017","journal-title":"Oncotarget"},{"key":"10.1016\/j.medj.2026.101103_bib80","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s44276-024-00048-8","article-title":"Characterizing functional DNA damage and response caused by the combination of CHK1 and WEE1 inhibitors in ovarian and breast cancer models","volume":"2","author":"Stewart","year":"2024","journal-title":"BJC Rep."},{"key":"10.1016\/j.medj.2026.101103_bib81","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2023.1271847","article-title":"Combined inhibition of Wee1 and Chk1 as a therapeutic strategy in multiple myeloma","volume":"13","author":"Bruyer","year":"2023","journal-title":"Front. Oncol."},{"key":"10.1016\/j.medj.2026.101103_bib82","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1038\/s41388-024-02939-z","article-title":"Synthetic lethal combination of CHK1 and WEE1 inhibition for treatment of castration-resistant prostate cancer","volume":"43","author":"Chao","year":"2024","journal-title":"Oncogene"},{"key":"10.1016\/j.medj.2026.101103_bib83","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1177\/02611929231157756","article-title":"Poor Translatability of Biomedical Research Using Animals - A Narrative Review","volume":"51","author":"Marshall","year":"2023","journal-title":"Altern. Lab. Anim."},{"key":"10.1016\/j.medj.2026.101103_bib84","first-page":"114","article-title":"Lost in translation: animal models and clinical trials in cancer treatment","volume":"6","author":"Mak","year":"2014","journal-title":"Am. J. Transl. Res."},{"key":"10.1016\/j.medj.2026.101103_bib85","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/nature03445","article-title":"Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy","volume":"434","author":"Farmer","year":"2005","journal-title":"Nature"},{"key":"10.1016\/j.medj.2026.101103_bib86","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1038\/nature03443","article-title":"Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase","volume":"434","author":"Bryant","year":"2005","journal-title":"Nature"},{"key":"10.1016\/j.medj.2026.101103_bib87","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1177\/1758834015616934","article-title":"Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy","volume":"8","author":"Eroglu","year":"2016","journal-title":"Ther. Adv. Med. Oncol."},{"key":"10.1016\/j.medj.2026.101103_bib101","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1002\/1097-0142(1967)20:2<233::AID-CNCR2820200209>3.0.CO;2-8","article-title":"Continuous infusion of methotrexate in children with acute leukemia","volume":"20","author":"Djerassi","year":"1967","journal-title":"Cancer"},{"key":"10.1016\/j.medj.2026.101103_bib102","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1038\/2121548a0","article-title":"Eradication of leukaemic cells (L1210) by methotrexate and methotrexate plus citrovorum factor","volume":"212","author":"Goldin","year":"1966","journal-title":"Nature"},{"key":"10.1016\/j.medj.2026.101103_bib88","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1111\/jcpt.13739","article-title":"Leucovorin (folinic acid) rescue for high-dose methotrexate: A review","volume":"47","author":"Jiang","year":"2022","journal-title":"J. Clin. Pharm. Ther."},{"key":"10.1016\/j.medj.2026.101103_bib89","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1634\/theoncologist.12-6-738","article-title":"Amifostine: the first selective-target and broad-spectrum radioprotector","volume":"12","author":"Kouvaris","year":"2007","journal-title":"Oncologist"},{"key":"10.1016\/j.medj.2026.101103_bib90","doi-asserted-by":"crossref","first-page":"2101","DOI":"10.1200\/JCO.1996.14.7.2101","article-title":"Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer","volume":"14","author":"Kemp","year":"1996","journal-title":"J. Clin. Oncol."},{"key":"10.1016\/j.medj.2026.101103_bib91","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1093\/neuonc\/not241","article-title":"Evaluation of amifostine for protection against cisplatin-induced serious hearing loss in children treated for average-risk or high-risk medulloblastoma","volume":"16","author":"Gurney","year":"2014","journal-title":"Neuro Oncol."},{"key":"10.1016\/j.medj.2026.101103_bib92","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1200\/JCO.23.02353","article-title":"Use of Sodium Thiosulfate as an Otoprotectant in Patients With Cancer Treated With Platinum Compounds: A Review of the Literature","volume":"42","author":"Meijer","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"10.1016\/j.medj.2026.101103_bib93","first-page":"309","article-title":"Delayed administration of sodium thiosulfate in animal models reduces platinum ototoxicity without reduction of antitumor activity","volume":"6","author":"Muldoon","year":"2000","journal-title":"Clin. Cancer Res."},{"key":"10.1016\/j.medj.2026.101103_bib94","doi-asserted-by":"crossref","first-page":"2376","DOI":"10.1056\/NEJMoa1801109","article-title":"Sodium thiosulfate for protection from cisplatin-induced hearing loss","volume":"378","author":"Brock","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.medj.2026.101103_bib95","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1007\/s12012-019-09554-5","article-title":"The Role of Topoisomerase II\u03b2 in the Mechanisms of Action of the Doxorubicin Cardioprotective Agent Dexrazoxane","volume":"20","author":"Hasinoff","year":"2020","journal-title":"Cardiovasc. Toxicol."},{"key":"10.1016\/j.medj.2026.101103_bib96","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1124\/jpet.119.264580","article-title":"Investigation of structure-activity relationships of dexrazoxane analogs reveals topoisomerase II\u03b2 interaction as a prerequisite for effective protection against anthracycline cardiotoxicity","volume":"373","author":"Koll\u00e1rov\u00e1-Br\u00e1zdov\u00e1","year":"2020","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"10.1016\/j.medj.2026.101103_bib97","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1200\/JCO.22.02423","article-title":"Dexrazoxane and Long-Term Heart Function in Survivors of Childhood Cancer","volume":"41","author":"Chow","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"10.1016\/j.medj.2026.101103_bib98","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1158\/1535-7163.MCT-15-0775","article-title":"Preclinical characterization of G1T28: A novel CDK4\/6 inhibitor for reduction of chemotherapy-induced myelosuppression","volume":"15","author":"Bisi","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"10.1016\/j.medj.2026.101103_bib99","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nature14664","article-title":"Comprehensive genomic profiles of small cell lung cancer","volume":"524","author":"George","year":"2015","journal-title":"Nature"},{"key":"10.1016\/j.medj.2026.101103_bib100","doi-asserted-by":"crossref","first-page":"12096","DOI":"10.1200\/JCO.2020.38.15_suppl.12096","article-title":"Myelopreservation and reduced use of supportive care with trilaciclib in patients with small cell lung cancer","volume":"38","author":"Weiss","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"10.1016\/j.medj.2026.101103_bib103","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2024.1336714","article-title":"Prevention of cisplatin-induced hearing loss in children: achievements and challenges for evidence-based implementation of sodium Thiosulfate","volume":"14","author":"Meijer","year":"2024","journal-title":"Front. Oncol."},{"key":"10.1016\/j.medj.2026.101103_bib104","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1038\/s41586-022-05213-y","article-title":"Brain-restricted mTOR inhibition with binary pharmacology","volume":"609","author":"Zhang","year":"2022","journal-title":"Nature"}],"container-title":["Med"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2666634026001066?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2666634026001066?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T02:10:53Z","timestamp":1783131053000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S2666634026001066"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5]]},"references-count":104,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["S2666634026001066"],"URL":"https:\/\/doi.org\/10.1016\/j.medj.2026.101103","relation":{},"ISSN":["2666-6340"],"issn-type":[{"value":"2666-6340","type":"print"}],"subject":[],"published":{"date-parts":[[2026,5]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Rethinking the role of synergy calculations in the next century of drug combination discovery","name":"articletitle","label":"Article Title"},{"value":"Med","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.medj.2026.101103","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 The Author(s). Published by Elsevier Inc.","name":"copyright","label":"Copyright"}],"article-number":"101103"}}