Rho GTPases in cancer resistance: mechanisms, vulnerabilities, and therapeutic opportunities

Intrinsic and adaptive resistance to therapy remain major barriers to effective cancer treatment. 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.