{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:56:28Z","timestamp":1790675788726,"version":"4.1.0"},"reference-count":47,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Werner syndrome helicase (WRN) is a synthetic lethal target for microsatellite instability (MSI) cancers. In part 1 of this ongoing first-in-human, phase 1 trial, escalating doses of RO7589831 (VVD-133214), a first-in-class, WRN covalent inhibitor, were evaluated in 88 patients with MSI and\/or deficient DNA mismatch repair advanced solid tumors. RO7589831 was administered once daily (150\u2009mg), twice daily (BID; 150\u20131,000\u2009mg) or three-times daily (TID; 200\u2013600\u2009mg). Primary objectives were to evaluate safety and tolerability, and identify the recommended phase 2 dose and schedule (RP2D). Secondary objectives included evaluation of antitumor activity (end points: disease control rate (DCR), objective response rate (ORR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS)). One dose-limiting toxicity of grade 2 nausea occurred in the 600-mg TID cohort; however, the maximum tolerated dose was not identified per protocol. Treatment-emergent adverse events (TEAEs) occurring in \u226510% were mostly grade 1\u20132; events in \u226530% were nausea (54.5%, 48\/88; grade 3+: 2.3%, 2\/88), diarrhea (43.2%, 38\/88; grade 3+: 1.1%, 1\/88), fatigue (39.8%, 35\/88; grade 3+: 2.3%, 2\/88), anemia (37.5%, 33\/88; grade 3+: 11.4%, 10\/88), and vomiting (30.7%, 27\/88, grade 3+: 1.1%, 1\/88). TEAEs leading to RO7589831 discontinuation were uncommon (3.4%, 3\/88). No grade 5 TEAEs occurred. The DCR among MSI efficacy-evaluable patients was 74.2% (49\/66). Seven patients achieved confirmed RECIST v.1.1 partial responses (ORR 10.6%, 7\/66); median DOR was 10.2+ months. Among MSI efficacy-evaluable patients, median PFS was 6.7 months (95% CI 4.1\u20138.5); median OS was 17.6 months (95% CI 17.6\u2013not estimable). Although direct target engagement in tumor tissue could not be demonstrated, exploratory analyses of ctDNA molecular response and FDG-PET metabolic response supported biological activity. The 150-mg and 600-mg BID doses were selected as RP2Ds for dose optimization. These data suggest that RO7589831 has a manageable safety profile and warrants further clinical testing. ClinicalTrials.gov identifier:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT06004245\" ext-link-type=\"uri\">NCT06004245<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41591-026-04657-3","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:04:21Z","timestamp":1790672661000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Werner helicase inhibitor for advanced microsatellite instability solid tumors: a phase 1 trial"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2154-3309","authenticated-orcid":false,"given":"Timothy A.","family":"Yap","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4991-9355","authenticated-orcid":false,"given":"Elisa","family":"Fontana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2606-1082","authenticated-orcid":false,"given":"Natalie","family":"Cook","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6554-5488","authenticated-orcid":false,"given":"Marwan","family":"Fakih","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0667-3284","authenticated-orcid":false,"given":"Oliver","family":"Bechter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2317-2721","authenticated-orcid":false,"given":"Erica S.","family":"Tsang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4921-829X","authenticated-orcid":false,"given":"Emiliano","family":"Calvo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5448-9003","authenticated-orcid":false,"given":"Kristoffer S.","family":"Rohrberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8137-5415","authenticated-orcid":false,"given":"Javier","family":"Ros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6396-630X","authenticated-orcid":false,"given":"Ignacio","family":"Matos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7579-1175","authenticated-orcid":false,"given":"John H.","family":"Strickler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malaka","family":"Ameratunga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meredith","family":"Pelster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3740-1612","authenticated-orcid":false,"given":"Adam","family":"Sharp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaspreet","family":"Grewal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Ulahannan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajesh","family":"Belani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7829-7065","authenticated-orcid":false,"given":"Matthew P.","family":"Patricelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia M.","family":"Blake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8960-5345","authenticated-orcid":false,"given":"David","family":"Dejardin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7331-3559","authenticated-orcid":false,"given":"Stephen","family":"Fowler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6377-4255","authenticated-orcid":false,"given":"Christina","family":"Godfried Sie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"Heller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Henkel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5810-1395","authenticated-orcid":false,"given":"Michael","family":"Hettich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"Lahr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Lamparter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Lane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne","family":"Meistermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8573-1248","authenticated-orcid":false,"given":"Christophe","family":"Meille","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Parrott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4690-0568","authenticated-orcid":false,"given":"Sotirios K.","family":"Sotiriou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Reeves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Romagnoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piergiorgio","family":"Pettazzoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Waterkamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1359-4795","authenticated-orcid":false,"given":"Matthias","family":"Wittwer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yali","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5562-1857","authenticated-orcid":false,"given":"Sophie","family":"Postel-Vinay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"4657_CR1","doi-asserted-by":"publisher","unstructured":"Bonneville, R. et al. Landscape of microsatellite instability across 39 cancer types. JCO Precis. Oncol. 1, 1\u201315 https:\/\/doi.org\/10.1200\/PO.17.00073 (2017).","DOI":"10.1200\/PO.17.00073"},{"key":"4657_CR2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15180","volume":"8","author":"I Cortes-Ciriano","year":"2017","unstructured":"Cortes-Ciriano, I., Lee, S., Park, W.-Y., Kim, T.-M. & Park, P. J. A molecular portrait of microsatellite instability across multiple cancers. Nat. Commun. 8, 15180 (2017).","journal-title":"Nat. Commun."},{"key":"4657_CR3","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1126\/science.aan6733","volume":"357","author":"DT Le","year":"2017","unstructured":"Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409\u2013413 (2017).","journal-title":"Science"},{"key":"4657_CR4","first-page":"PO.20.00456","volume":"5","author":"A Keshinro","year":"2021","unstructured":"Keshinro, A. et al. Tumor-infiltrating lymphocytes, tumor mutational burden, and genetic alterations in microsatellite unstable, microsatellite stable, or mutant POLE\/POLD1 colon cancer. JCO Precis. Oncol. 5, PO.20.00456 (2021).","journal-title":"JCO Precis. Oncol"},{"key":"4657_CR5","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.1093\/annonc\/mdz116","volume":"30","author":"C Luchini","year":"2019","unstructured":"Luchini, C. et al. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1\/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann. Oncol. 30, 1232\u20131243 (2019).","journal-title":"Ann. Oncol."},{"key":"4657_CR6","doi-asserted-by":"publisher","first-page":"e2200179","DOI":"10.1200\/PO.22.00179","volume":"7","author":"C Gutierrez","year":"2023","unstructured":"Gutierrez, C., Ogino, S., Meyerhardt, J. A. & Bryan Iorgulescu, J. The prevalence and prognosis of microsatellite instability-high\/mismatch repair-deficient colorectal adenocarcinomas in the United States. JCO Precis. Oncol. 7, e2200179 (2023).","journal-title":"JCO Precis. Oncol."},{"key":"4657_CR7","doi-asserted-by":"publisher","DOI":"10.1016\/j.prp.2023.154366","volume":"243","author":"F Zannier","year":"2023","unstructured":"Zannier, F. et al. Impact of DNA mismatch repair proteins deficiency on number and ratio of lymph nodal metastases in colorectal adenocarcinoma. Pathol. Res. Pract. 243, 154366 (2023).","journal-title":"Pathol. Res. Pract."},{"key":"4657_CR8","doi-asserted-by":"publisher","unstructured":"Banerjee, S. et al. Real-world demographics and survival outcomes of patients in England with advanced or recurrent endometrial cancer by mismatch repair status. Gynecol. Oncol. Rep. 66, 102148 https:\/\/doi.org\/10.1016\/j.gore.2026.102148 (2026).","DOI":"10.1016\/j.gore.2026.102148"},{"key":"4657_CR9","doi-asserted-by":"publisher","first-page":"e2400815","DOI":"10.1200\/PO-24-00815","volume":"9","author":"Y Chen","year":"2025","unstructured":"Chen, Y., Lubinga, S. J., Williams, T., Carlson, J. J. & Ramsey, S. Real-world molecular testing rates and patterns in patients with primary advanced or recurrent endometrial cancer in the United States. JCO Precis. Oncol. 9, e2400815 (2025).","journal-title":"JCO Precis. Oncol."},{"key":"4657_CR10","doi-asserted-by":"publisher","first-page":"2833","DOI":"10.1007\/s00404-024-07504-3","volume":"309","author":"SS Kelkar","year":"2024","unstructured":"Kelkar, S. S. et al. Real-world prevalence of microsatellite instability testing and related status in women with advanced endometrial cancer in Europe. Arch. Gynecol. Obstet. 309, 2833\u20132841 (2024).","journal-title":"Arch. Gynecol. Obstet."},{"key":"4657_CR11","doi-asserted-by":"publisher","first-page":"2207","DOI":"10.1056\/NEJMoa2017699","volume":"383","author":"T Andr\u00e9","year":"2020","unstructured":"Andr\u00e9, T. et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N. Engl. J. Med. 383, 2207\u20132218 (2020).","journal-title":"N. Engl. J. Med."},{"key":"4657_CR12","doi-asserted-by":"publisher","first-page":"2014","DOI":"10.1056\/NEJMoa2402141","volume":"391","author":"T Andre","year":"2024","unstructured":"Andre, T. et al. Nivolumab plus ipilimumab in microsatellite-instability-high metastatic colorectal cancer. N. Engl. J. Med. 391, 2014\u20132026 (2024).","journal-title":"N. Engl. J. Med."},{"key":"4657_CR13","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/S0140-6736(24)02848-4","volume":"405","author":"T Andr\u00e9","year":"2025","unstructured":"Andr\u00e9, T. et al. Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial. Lancet 405, 383\u2013395 (2025).","journal-title":"Lancet"},{"key":"4657_CR14","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1016\/S1470-2045(22)00197-8","volume":"23","author":"LA Diaz","year":"2022","unstructured":"Diaz, L. A. et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 23, 659\u2013670 (2022).","journal-title":"Lancet Oncol."},{"key":"4657_CR15","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/j.ygyno.2024.12.020","volume":"193","author":"DM O\u2019Malley","year":"2025","unstructured":"O\u2019Malley, D. M. et al. Pembrolizumab in microsatellite instability-high\/mismatch repair deficient (MSI-H\/dMMR) and non-MSI-H\/non-dMMR advanced endometrial cancer: phase 2 KEYNOTE-158 study results. Gynecol. Oncol. 193, 130\u2013135 (2025).","journal-title":"Gynecol. Oncol."},{"key":"4657_CR16","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1016\/j.annonc.2022.05.519","volume":"33","author":"M Maio","year":"2022","unstructured":"Maio, M. et al. Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study. Ann. Oncol. 33, 929\u2013938 (2022).","journal-title":"Ann. Oncol."},{"key":"4657_CR17","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1038\/s43018-024-00894-y","volume":"6","author":"A Marabelle","year":"2025","unstructured":"Marabelle, A. et al. Pembrolizumab in microsatellite-instability-high and mismatch-repair-deficient advanced solid tumors: updated results of the KEYNOTE-158 trial. Nat. Cancer 6, 253\u2013258 (2025).","journal-title":"Nat. Cancer"},{"key":"4657_CR18","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1016\/j.annonc.2026.03.005","volume":"37","author":"C Cremolini","year":"2026","unstructured":"Cremolini, C. et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann. Oncol. 37, 759\u2013776 (2026).","journal-title":"Ann. Oncol."},{"key":"4657_CR19","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1016\/j.annonc.2022.05.009","volume":"33","author":"A Oaknin","year":"2022","unstructured":"Oaknin, A. et al. Endometrial cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann. Oncol. 33, 860\u2013877 (2022).","journal-title":"Ann. Oncol."},{"key":"4657_CR20","doi-asserted-by":"publisher","first-page":"5497","DOI":"10.1158\/0008-5472.CAN-12-2975","volume":"73","author":"M Aggarwal","year":"2013","unstructured":"Aggarwal, M. et al. Werner syndrome helicase has a critical role in DNA damage responses in the absence of a functional fanconi anemia pathway. Cancer Res. 73, 5497\u20135507 (2013).","journal-title":"Cancer Res."},{"key":"4657_CR21","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1083\/jcb.200705126","volume":"180","author":"LM Pirzio","year":"2008","unstructured":"Pirzio, L. M., Pichierri, P., Bignami, M. & Franchitto, A. Werner syndrome helicase activity is essential in maintaining fragile site stability. J. Cell Biol. 180, 305\u2013314 (2008).","journal-title":"J. Cell Biol."},{"key":"4657_CR22","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1038\/s41586-019-1103-9","volume":"568","author":"FM Behan","year":"2019","unstructured":"Behan, F. M. et al. Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature 568, 511\u2013516 (2019).","journal-title":"Nature"},{"key":"4657_CR23","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1038\/s41586-019-1102-x","volume":"568","author":"EM Chan","year":"2019","unstructured":"Chan, E. M. et al. WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature 568, 551\u2013556 (2019).","journal-title":"Nature"},{"key":"4657_CR24","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1016\/j.isci.2019.02.006","volume":"13","author":"L Kategaya","year":"2019","unstructured":"Kategaya, L., Perumal, S. K., Hager, J. H. & Belmont, L. D. Werner syndrome helicase is required for the survival of cancer cells with microsatellite instability. iScience 13, 488\u2013497 (2019).","journal-title":"iScience"},{"key":"4657_CR25","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.43333","volume":"8","author":"S Lieb","year":"2019","unstructured":"Lieb, S. et al. Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells. Elife 8, e43333 (2019).","journal-title":"Elife"},{"key":"4657_CR26","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1038\/s41586-020-2769-8","volume":"586","author":"N van Wietmarschen","year":"2020","unstructured":"van Wietmarschen, N. et al. Repeat expansions confer WRN dependence in microsatellite-unstable cancers. Nature 586, 292\u2013298 (2020).","journal-title":"Nature"},{"key":"4657_CR27","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1038\/s41586-024-07318-y","volume":"629","author":"KA Baltgalvis","year":"2024","unstructured":"Baltgalvis, K. A. et al. Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase. Nature 629, 435\u2013442 (2024).","journal-title":"Nature"},{"key":"4657_CR28","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.1158\/2159-8290.CD-24-0052","volume":"14","author":"G Picco","year":"2024","unstructured":"Picco, G. et al. Novel WRN helicase inhibitors selectively target microsatellite-unstable cancer cells. Cancer Discov. 14, 1457\u20131475 (2024).","journal-title":"Cancer Discov."},{"key":"4657_CR29","doi-asserted-by":"publisher","first-page":"S605","DOI":"10.1016\/j.annonc.2025.08.1494","volume":"36","author":"MBB Foote","year":"2025","unstructured":"Foote, M. B. B. et al. First-in-human phase I\/Ib study of the oral Werner (WRN) helicase inhibitor HRO761 in patients (pts) with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) advanced solid tumors: Interim safety and efficacy analysis from HRO761 single agent dose escalation. Ann. Oncol. 36, S605\u2013S606 (2025).","journal-title":"Ann. Oncol."},{"key":"4657_CR30","doi-asserted-by":"publisher","first-page":"4882","DOI":"10.1158\/1078-0432.CCR-25-1918","volume":"31","author":"OO Okusanya","year":"2025","unstructured":"Okusanya, O. O. et al. FDA-AACR strategies for optimizing dosages for oncology drug products: early-phase trials using innovative trial designs and biomarkers. Clin. Cancer Res. 31, 4882\u20134890 (2025).","journal-title":"Clin. Cancer Res."},{"key":"4657_CR31","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1101\/gad.351085.123","volume":"37","author":"D Zong","year":"2023","unstructured":"Zong, D. et al. Comprehensive mapping of cell fates in microsatellite unstable cancer cells supports dual targeting of WRN and ATR. Genes Dev. 37, 913\u2013928 (2023).","journal-title":"Genes Dev."},{"key":"4657_CR32","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10460-1","volume":"10","author":"H Fleury","year":"2019","unstructured":"Fleury, H. et al. Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence. Nat. Commun. 10, 2556 (2019).","journal-title":"Nat. Commun."},{"key":"4657_CR33","doi-asserted-by":"publisher","unstructured":"Orcholski, M. E. et al. Anticipating on-target resistance to WRN inhibitors in microsatellite unstable cancers. Preprint at bioRxiv https:\/\/doi.org\/10.64898\/2026.01.22.700152 (2026).","DOI":"10.64898\/2026.01.22.700152"},{"key":"4657_CR34","doi-asserted-by":"publisher","first-page":"B003","DOI":"10.1158\/1535-7163.TARG-25-B003","volume":"24","author":"C Lemech","year":"2025","unstructured":"Lemech, C. et al. Orally administered MOMA-341 as monotherapy or combination therapy in participants with advanced or metastatic solid tumors: phase 1 study design. Mol. Cancer Ther. 24, B003 (2025).","journal-title":"Mol. Cancer Ther"},{"key":"4657_CR35","doi-asserted-by":"publisher","first-page":"S627","DOI":"10.1016\/j.annonc.2025.08.1598","volume":"36","author":"J Nemunaitis","year":"2025","unstructured":"Nemunaitis, J. et al. A phase I\/II open-label study of NDI-219216, a WRN inhibitor, in patients with advanced solid tumors with or without microsatellite instability\/deficient mismatch repair. Ann. Oncol. 36, S627\u2013S628 (2025).","journal-title":"Ann. Oncol."},{"key":"4657_CR36","doi-asserted-by":"publisher","first-page":"CT194","DOI":"10.1158\/1538-7445.AM2025-CT194","volume":"85","author":"V Samnotra","year":"2025","unstructured":"Samnotra, V. et al. First-in-human, phase 1\/2 study of GSK4418959, an oral Werner DNA helicase inhibitor, alone or combined with other anticancer agents in adults with advanced mismatch repair-deficient or microsatellite instability-high solid tumors (SYLVER). Cancer Res. 85, CT194 (2025).","journal-title":"Cancer Res."},{"key":"4657_CR37","doi-asserted-by":"publisher","first-page":"TPS3173","DOI":"10.1200\/JCO.2026.44.16_suppl.TPS3173","volume":"44","author":"E Won","year":"2026","unstructured":"Won, E., Tran, Q., Hollstein, P. E. & Katlinskaya, Y. A multicenter phase 1\/1b study of AMG 436 as monotherapy and combination therapy in patients with advanced MSI-H\/dMMR solid tumors. J. Clin. Oncol. 44, TPS3173 (2026).","journal-title":"J. Clin. Oncol."},{"key":"4657_CR38","doi-asserted-by":"publisher","first-page":"TPS3170","DOI":"10.1200\/JCO.2026.44.16_suppl.TPS3170","volume":"44","author":"TA Yap","year":"2026","unstructured":"Yap, T. A. et al. Phase 1\/2 study of the novel Werner helicase inhibitor EIK1005 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors, including MSI-H or dMMR tumors. J. Clin. Oncol. 44, TPS3170 (2026).","journal-title":"J. Clin. Oncol."},{"key":"4657_CR39","doi-asserted-by":"publisher","unstructured":"Picco, G. et al. On-target mutations confer resistance to WRN helicase inhibitors in microsatellite unstable cancer cells. Preprint at bioRxiv https:\/\/doi.org\/10.64898\/2025.12.23.695783 (2025).","DOI":"10.64898\/2025.12.23.695783"},{"key":"4657_CR40","doi-asserted-by":"publisher","first-page":"1865","DOI":"10.1038\/s41401-021-00798-y","volume":"43","author":"H-X Zou","year":"2022","unstructured":"Zou, H.-X. et al. Effect of autoinduction and food on the pharmacokinetics of furmonertinib and its active metabolite characterized by a population pharmacokinetic model. Acta Pharmacol. Sin. 43, 1865\u20131874 (2022).","journal-title":"Acta Pharmacol. Sin."},{"key":"4657_CR41","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50178-3","volume":"15","author":"F Rodr\u00edguez P\u00e9rez","year":"2024","unstructured":"Rodr\u00edguez P\u00e9rez, F. et al. WRN inhibition leads to its chromatin-associated degradation via the PIAS4-RNF4-p97\/VCP axis. Nat. Commun. 15, 6059 (2024).","journal-title":"Nat. Commun."},{"key":"4657_CR42","doi-asserted-by":"publisher","first-page":"e0264138","DOI":"10.1371\/journal.pone.0264138","volume":"17","author":"CA Milbury","year":"2022","unstructured":"Milbury, C. A. et al. Clinical and analytical validation of FoundationOne\u00aeCDx, a comprehensive genomic profiling assay for solid tumors. PLoS ONE 17, e0264138 (2022).","journal-title":"PLoS ONE"},{"key":"4657_CR43","doi-asserted-by":"publisher","first-page":"e0237802","DOI":"10.1371\/journal.pone.0237802","volume":"15","author":"R Woodhouse","year":"2020","unstructured":"Woodhouse, R. et al. Clinical and analytical validation of FoundationOne Liquid CDx, a novel 324-Gene cfDNA-based comprehensive genomic profiling assay for cancers of solid tumor origin. PLoS ONE 15, e0237802 (2020).","journal-title":"PLoS ONE"},{"key":"4657_CR44","doi-asserted-by":"publisher","first-page":"2452","DOI":"10.1158\/1078-0432.CCR-23-3321","volume":"30","author":"CD Rolfo","year":"2024","unstructured":"Rolfo, C. D. et al. Measurement of ctDNA tumor fraction identifies informative negative liquid biopsy results and informs value of tissue confirmation. Clin. Cancer Res. 30, 2452\u20132460 (2024).","journal-title":"Clin. Cancer Res."},{"key":"4657_CR45","doi-asserted-by":"publisher","first-page":"e0302129","DOI":"10.1371\/journal.pone.0302129","volume":"19","author":"DR Zollinger","year":"2024","unstructured":"Zollinger, D. R. et al. Analytical validation of a novel comprehensive genomic profiling informed circulating tumor DNA monitoring assay for solid tumors. PLoS ONE 19, e0302129 (2024).","journal-title":"PLoS ONE"},{"key":"4657_CR46","doi-asserted-by":"publisher","first-page":"3142","DOI":"10.1200\/JCO.2025.43.16_suppl.3142","volume":"43","author":"MA George","year":"2025","unstructured":"George, M. A. et al. Clinical performance of Signatera Genome assay in a cohort of patients (pts) with solid tumors. J. Clin. Oncol. 43, 3142 (2025).","journal-title":"J. Clin. Oncol."},{"key":"4657_CR47","doi-asserted-by":"publisher","first-page":"1773","DOI":"10.1016\/S0959-8049(99)00229-4","volume":"35","author":"H Young","year":"1999","unstructured":"Young, H. et al. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur. J. Cancer 35, 1773\u20131782 (1999).","journal-title":"Eur. J. Cancer"}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04657-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04657-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04657-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:04:22Z","timestamp":1790672662000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04657-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":47,"alternative-id":["4657"],"URL":"https:\/\/doi.org\/10.1038\/s41591-026-04657-3","relation":{},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]},"assertion":[{"value":"27 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 August 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 September 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"T.A.Y. discloses employment (University of Texas MD Anderson Cancer Center), consultancy (AbbVie, Acrivon, Adagene, Almac, Aduro, Amphista, Artios, Astex, AstraZeneca, Athena, Atrin, Avenzo, Avoro, Axiom, Baptist Health Systems, Bayer, BeiGene, BioCity Pharma, Blueprint, Boxer, BMS, C4 Therapeutics, Calithera, Cancer Research UK, Carrick Therapeutics, Circle Pharma, Clovis, Cybrexa, Daiichi Sankyo, Dark Blue Therapeutics, Diffusion, Duke Street Bio, 858 Therapeutics, EcoR1 Capital, Ellipses Pharma, EMD Serono, Entos, F-Star, Genesis Therapeutics, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Guidepoint, Ideaya Biosciences, Idience, Ignyta, I-Mab, ImmuneSensor, Impact Therapeutics, Institut Gustave Roussy, Intellisphere, Jansen, Kyn, MEI pharma, Mereo, MSD, Merit, Monte Rosa Therapeutics, Natera, Nested Therapeutics, Nexys, Nimbus, Novocure, Odyssey, OHSU, OncoSec, Ono Pharma, Onxeo, PanAngium Therapeutics, Pegascy, PER, Pfizer, Piper-Sandler, Pliant Therapeutics, Prolynx, Radiopharma Theranostics, Repare, resTORbio, Roche, Ryvu Therapeutics, SAKK, Sanofi, Schrodinger, Servier, Synnovation, Synthis Therapeutics, Tango, TCG Crossover, TD2, Terremoto Biosciences, Tessellate Bio, Theragnostics, Terns Pharmaceuticals, Tolremo, Tome, Thryv Therapeutics, Trevarx Biomedical, Varian, Veeva, Versant, Vibliome, Voronoi, Xinthera, Zai Labs and ZielBio) and research funding (Acrivon, Artios, AstraZeneca, Bayer, BeiGene, BioNTech, Blueprint, BMS, Boundless Bio, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GSK, Genentech, Haihe, Ideaya ImmuneSensor, Insilico Medicine, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, MSD, Mirati, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tango, Tesaro, Vivace and Zenith) and grants (NCI, US Department of Defence and V Foundation for Cancer Research). E.F. discloses support for attending meetings and\/or travel (BicycleTx, CARIS Life Science, Erasca, Repare Therapeutics, Sapience and Seagen), advisory committees (Astellas, Bayer, BeOne, BicycleTx, BMS, Erasca and Pfizer) and other (Acerta Pha, ADC Therapeutics, Alterome, Amgen, Apollo therapeutics, Arcus Bioscience, Array Biopharma, Artios Pharma, Astellas, Astex, AstraZeneca, Aveo Pharmaceuticals, Basilea Pharmaceutica, Bayer, BeiGene, Bicycle Therapeutics, Bioinvent, BioNTech SE, BluePrint, BMS, Boehringer Ingelheim, Calithera, Carrick Therapeutics, Casi Therapeutics, Cellcentric, Clovis Oncology, Crescendo Biologics, Cronos Bio, CytomX Therapeutics, Daiichi Sankyo, Deciphera, ED Therapeutics, Eli Lilly, Elipsees, Erasca, Exelixis, Fore Biotherapeutics, G1 Therapeutics, Gilead Science, GSK, H3 Biomedicine, HUTCHMED, Immunocore, Immunomedics, Incyte, Instil Bio, Iovance, Janssen, Jiangsu Hengrui Medicine, Keros Therapeutics, Lupin, Macrogenics, Menarini, Merck KGaA, Mereo Biopharma, Merus, MIllenium Pharmaceuticals, MSD, Nerviano Medica, Nurix Therapeutics, Oncologie, Oxford Vacmedix, Pfizer, Plexxikon, PMV Pharma, PMV Pharmaceuticals, Pyxis Oncology, Relay Therapeutics, Repair Therapeutics, Ribon Therapeutics, Roche\/Genentech, Sapience Pharma, Seagen, Servier, SK, Synthon Biopharmaceuticals, Taiho Pharmaceutical, Takeda, Tesaro and Turning Point Therapeutics; all funds to institution). N.C. discloses research support (UK National Institute for Health and Care Research (NIHR) Manchester Clinical Research Facility and the Manchester Experimental Cancer Medicine Centre award. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care), consultancy (Roche, Servier), research funding (AstraZeneca, Avacta, Bayer, Boehringer Ingelheim, Eisai, LOXO-Oncology, MSD, Novartis, Orion, RedX Pharmaceuticals, Roche, Starpharma, Taiho, UCB), honoraria (Roche) and speaker\u2019s bureau (Roche). M.F. discloses consultancy (AbbVie, Adagene, BMS, Delcath, Iterion Therapeutics, MSD, Microbial Machines, Revolution Medicines, Summit Therapeutics, Taiho Oncology and Totus Medicines) and advisory committees (Exelixis, J&J, Merus N.V., Roche\/Genentech, Tempus and Xilio). O.B. discloses advisory committees (Pierre Fabre). E.S.T. discloses research funding (Roche). E.C. discloses employment (START and HM Hospitales), stock and other ownership interests (START, HM Hospitales and Oncoart Associated), consultancy or advisory role (AbbVie, Aromics, AstraZeneca, Anaveon, Column Group, Chugai, Debiopharm Group, Ellipses Pharma, Genmab, Grey Wolf Therapeutics, Incyte, Janssen, Kivu, Medsir, MonTa, Roche\/Genentech, Servier and TargImmune), research funding (START) and other (Foundation INTHEOS, Foundation PharmaMar and CRIS Cancer Foundation). K.S.R. discloses research funding (Alligator Bioscience, Amgen, AstraZeneca, Bayer, Bioinvent, Biontech, Black Diamond Therapeutics, BMS, CDR life, Eikon Therapeutics, Daiichi Sankyo, Genmab, GSK, Incyte, Lilly, Monta Bioscience, MSD, Navire, Novartis, Pfizer, Repare Therapeutics, Roche\/Genentech and Servier; all funds to institution), honoraria (AstraZeneca, MSD and GSK) and advisory committees (AbbVie, Genmab and MSD); J.R. discloses employment (Vall Hebron Institute of Oncology), honoraria (Amgen, BMS, Pfizer, MSD, Sanofi and Takeda) and travel and accommodation expenses (Amgen, MSD, Pierre Fabre, Servier and Takeda). I.M. discloses employment (Cl\u00ednica Universidad de Navarra), consultancy (AstraZeneca) and speaker\u2019s bureau (MSD). J.H.S. discloses consultancy (AbbVie, Alterome, Amgen, Astellas, AstraZeneca, Bayer, BeOne, Boehringer Ingelheim, BMS, Cytovation, Daiichi Sankyo, Eli Lilly, Exelixis, Full-Life Technologies, GE Healthcare, GSK, Incyte, Ipsen, J&J, Jazz Pharmaceuticals, Leap, MSD, Natera, Pfizer, Pheon Therapeutics, Quanta Therapeutics, Roche\/Genentech, Regeneron, Revolution Medicines, Sanofi, Taiho, Takeda and Tempus), equity (Triumvira Immunologics) and research funding (AbbVie, Amgen, Alterome, Apollo Therapeutics, Astellas, Bayer, BeOne, Daiichi Sankyo, Eli Lilly, Erasca, GSK, Leap Therapeutics, Novartis, Pfizer, Quanta Therapeutics, Regeneron, Revolution Medicines and Roche\/Genentech). M.A. discloses grants or contracts (AACR, Alpha-9 Theranostics, Antengene, Beigene, Iqvia, Medpace, Monash Partners Comprehensive Cancer Consortium, Novotech, Pharmaceutical Research Associates, Roche, Senz Oncology and Servier; all funds to institution). M.P. discloses consultancy (BeOne Medicines, BMS, Curio Science, CytomX, Roche\/Genentech, Kura Oncology, Novocure, Onviv, Pfizer, Revolution Medicines and Takeda; all funds to institution) and research funding (AbbVie, Accent Therapeutics, Acepodia Biotech, Affini-T Therapeutics, Agenus, Arcus Biosciences, Astellas, AstraZeneca, BeiGene, BioNTech, Boehringer Ingelheim, Chimeric Therapeutics, Coherus BioSciences, Compass Therapeutics, CytomX, Daiichi Sankyo, DynamiCure Biotechnology, Elevation Oncology, Elicio Therapeutics, Fate Therapeutics, Fog Pharmaceuticals, Frontier Medicines, GlaxoSmithKline, HiberCell, Immune-Onc Therapeutics, Impact Therapeutics, Institut de Recherches Internationales Servier, Ipsen, Janssen, Jazz Pharmaceuticals, Kura Oncology, Leap Therapeutics, Marengo Therapeutics, MediLink Therapeutics, Panbela Therapeutics, Quanta Therapeutics, Recursion Pharmaceuticals, Renovo, Revolution Medicines, Roche, SeaGen, SQZ Biotechnologies, Tachyon Therapeutics, Takeda, TORL Biotherapeutics, TransThera Sciences, ZielBio and 1200 Pharma; all funds to institution). A.S. discloses employment (Institute of Cancer Research), consultancy (AbbVie, CHARM therapeutics, DE Shaw, Droia Ventures and Ellipses Pharma), honoraria (Astellas, MSD), advisory committees (Delphia Therapeutics, Monte Rosa Therapeutics and ProBio study) and travel and accommodation (AbbVie, Nurix, Roche\/Genetech and Sanofi). J.G. discloses speaker\u2019s bureau (BMS). S.U. discloses research support (AbbVie, Adlai Nortye, ArQule, AstraZeneca, Atreca, Boehringer Ingelheim, BMS, Celgene, Ciclomed, Erasca, Evelo Biosciences, Exelexis, ExTheraMedical, G1 Therapeutics, GSK, IGM biosciences, Incyte, Isofol, Klus Pharma, Macrogenics, MSD, Mersana Therapeutics, OncoMed Pharmaceuticals, Pfizer, Qurgen, Regeneron, Revolution Medicines, Sapience Therapeutics, Synermore Biologics Co., Takeda, Tarveda Therapeutics, Tesaro, Tempest and Vigeo Therapeutics; all funds to institution) and advisory committees (Tapur study). R.B. discloses employment (Vividion Therapeutics) and equity (Amgen). M.P.P. discloses employment (Vividion Therapeutics). S.M.B. discloses employment (Roche) and equity (Roche). D.D. discloses employment (Roche), equity (Roche) and patents and royalties (Roche). S.F. discloses employment (Roche) and equity (Roche). C.G.S. discloses employment (Roche) and equity (Roche). A.H. discloses employment (Roche) and equity (Roche). N.H. discloses employment (Roche). M.H. discloses employment (Roche) and equity (Roche). A.L. discloses employment (Roche) and patents and royalties (Roche). D.L. discloses employment (Roche) and equity (Roche). C.L. discloses employment (Roche) and equity (Roche and GSK). T.L. discloses employment (Roche) and equity (Roche). H.M. discloses employment (Roche). C.M. discloses employment (Roche) and equity (Roche). N.P. discloses employment (Roche) and equity (Roche). S.K.S. discloses employment (Roche) and equity (Roche, FoRx Therapeutics). D.R. discloses employment (Roche) and equity (Roche). B.R. discloses past employment (Roche), equity (Roche) and patents and royalties (Roche). P.P. discloses past employment (Roche) and equity (Roche). D.W. discloses employment (Roche) and equity (Roche). M.W. discloses employment (Roche) and equity (Roche). Y.F. discloses employment (Roche) and equity (Roche). S.P.-V. discloses consultancy (EPICS therapeutics) and research funding (Amgen, AstraZeneca, Clever Peptide, Novartis, Oxford Biotherapeutics and Roche; all funds to institution).","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}