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Diverse resistance mechanisms, including epithelial-mesenchymal transition, enhanced tolerance to DNA damage, impaired cell death pathways, metabolic reprogramming, and cues from the tumour microenvironment, are increasingly recognised as being tightly integrated with Rho GTPase signalling networks. Accumulating evidence positions these pathways as central regulators of therapeutic resistance across multiple cancer types. In this review, we synthesise recent experimental findings linking Rho GTPase-mediated signalling to therapy resistance and evaluate emerging strategies aimed at targeting these signalling axes. We critically examine the translational readiness of approaches that directly inhibit Rho GTPases, disrupt downstream effector pathways, or modulate canonical regulators such as RhoGEFs and RhoGAPs, and discuss the key challenges and opportunities associated with their clinical deployment. Collectively, these insights highlight the therapeutic potential of targeting Rho GTPase signalling as a foundation for next-generation cancer treatments.<\/jats:p>","DOI":"10.1042\/bst20250097","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T07:58:05Z","timestamp":1778140685000},"page":"461-476","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Rho GTPases in cancer resistance: mechanisms, vulnerabilities, and therapeutic opportunities"],"prefix":"10.1042","volume":"54","author":[{"given":"Amy","family":"Beaudin","sequence":"first","affiliation":[{"name":"1D\u00e9partement de biologie mol\u00e9culaire, biochimie m\u00e9dicale et pathologie, Facult\u00e9 de m\u00e9decine, Universit\u00e9 Laval, Qu\u00e9bec, QC, Canada"},{"name":"2Oncology Research program, CHU de Qu\u00e9bec - Universit\u00e9 Laval Research Center, Qu\u00e9bec, QC, Canada"},{"name":"3Centre de recherche sur le cancer de l'Universit\u00e9 Laval (CRC), Qu\u00e9bec, QC, Canada"},{"name":"4Centre de recherche en organog\u00e9n\u00e8se exp\u00e9rimentale (LOEX), Qu\u00e9bec, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Lefran\u00e7ois","sequence":"additional","affiliation":[{"name":"5Cancer Axis, Lady Davis Institute for Medical Research, Montreal, QC, Canada"},{"name":"6Division of Experimental Medicine, McGill University, Montreal, QC, Canada"},{"name":"7Division of Dermatology, Department of Medicine, McGill University, Montreal, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7198-3257","authenticated-orcid":false,"given":"M\u00e9lanie","family":"Laurin","sequence":"additional","affiliation":[{"name":"1D\u00e9partement de biologie mol\u00e9culaire, biochimie m\u00e9dicale et pathologie, Facult\u00e9 de m\u00e9decine, Universit\u00e9 Laval, Qu\u00e9bec, QC, Canada"},{"name":"2Oncology Research program, CHU de Qu\u00e9bec - Universit\u00e9 Laval Research Center, Qu\u00e9bec, QC, Canada"},{"name":"3Centre de recherche sur le cancer de l'Universit\u00e9 Laval (CRC), Qu\u00e9bec, QC, Canada"},{"name":"4Centre de recherche en organog\u00e9n\u00e8se exp\u00e9rimentale (LOEX), Qu\u00e9bec, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"2026050703575915200_B1","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1152\/physrev.00045.2020","article-title":"RHO GTPase signaling in cancer progression and dissemination","volume":"102","author":"Crosas-Molist","year":"2022","journal-title":"Physiological Rev."},{"key":"2026050703575915200_B2","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1080\/21541248.2017.1391365","article-title":"Fast-cycling Rho GTPases","volume":"11","author":"Aspenstr\u00f6m","year":"2020","journal-title":"Small GTPases"},{"key":"2026050703575915200_B3","doi-asserted-by":"publisher","first-page":"117337","DOI":"10.1016\/j.bmc.2023.117337","article-title":"Advances in the development of Rho GTPase inhibitors","volume":"90","author":"Zhang","year":"2023","journal-title":"Bioorganic Medicinal Chem."},{"key":"2026050703575915200_B4","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1080\/21541248.2016.1173767","article-title":"Deregulation of Rho GTPases in cancer","volume":"7","author":"Porter","year":"2016","journal-title":"Small GTPases"},{"key":"2026050703575915200_B5","doi-asserted-by":"publisher","first-page":"5950","DOI":"10.1038\/s41388-021-01985-1","article-title":"RAC1 plays an essential role in estrogen receptor alpha function in breast cancer cells","volume":"40","author":"Sun","year":"2021","journal-title":"Oncogene"},{"key":"2026050703575915200_B6","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1038\/s41419-023-05702-6","article-title":"TRIM56 acts through the IQGAP1\u2013CDC42 signaling axis to promote glioma cell migration and invasion","volume":"14","author":"Zhang","year":"2023","journal-title":"Cell Death Dis."},{"key":"2026050703575915200_B7","doi-asserted-by":"publisher","first-page":"1716","DOI":"10.7150\/ijbs.56694","article-title":"NDRG1 regulates Filopodia-induced colorectal cancer invasiveness via modulating CDC42 activity","volume":"17","author":"Aikemu","year":"2021","journal-title":"Int. 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