Reframing cancer drug resistance: transporters, persister cells, senescence, and emerging therapeutic strategies

Cancer drug resistance remains one of the greatest barri­ers to durable therapeutic success. Here, we reframe resis­tance as a dynamic landscape shaped by transporter‑me­diated efflux, reversible drug‑tolerant persister states, and therapy‑induced senescence. This review highlights areas where our group has made substantial contributions, with a particular focus on our own experimental and conceptual advances. We show how P‑glycoprotein (P-gp) overexpres­sion, traditionally viewed as an obstacle sustaining cancer multidrug resistance (MDR), creates exploitable metabolic vulnerabilities, enabling the development of MDR‑selective compounds. We demonstrate that persister cells rely on transient P‑gp–mediated detoxification, revealing a thera­peutic window during drug‑free intervals. We further show that senescence is not a terminal fate but a relapse‑initi­ating state requiring targeted intervention. Finally, we il­lustrate how pharmacokinetics and dosing schedules can be harnessed to reshape tumor evolution, culminating in LiPyDau, a next‑generation liposomal anthracycline with durable activity against resistant tumors. Together, these insights outline a unified strategy for anticipating, inter­cepting, and ultimately overcoming cancer drug resistance.

Magy Onkol 70:118-127, 2026