Beyond STMN1: stathmin-family control of microtubule dynamics and paclitaxel resistance in cancer.

Paclitaxel is a cornerstone microtubule-stabilizing agent, but intrinsic and acquired resistance limit durable benefit. Resistance emerges from interacting changes in drug transport, tubulin composition, microtubule regulation, mitotic fate, apoptosis, autophagy, cellular plasticity and the tumor microenvironment. The stathmin family-STMN1, STMN2, STMN3 and STMN4-controls microtubule assembly through tubulin sequestration and catastrophe-promoting activity and therefore occupies a direct functional interface with paclitaxel pharmacodynamics. STMN1 has the strongest evidence: overexpression can reduce taxane sensitivity, whereas suppression restores microtubule stabilization and drug response in several experimental systems; clinical studies also associate high STMN1 with unfavorable outcome or reduced taxane benefit in selected cancers. Evidence for STMN3 is narrower but includes a mechanistically relevant ovarian-cancer study in which bisphosphorylated PEA-15 sensitized cells to paclitaxel by attenuating SCLIP/STMN3-mediated microtubule destabilization. By contrast, direct evidence for STMN2 and STMN4 in taxane response remains insufficient. This review develops a microtubule-centered resistance model, distinguishes established findings from context-dependent observations and testable hypotheses, and evaluates biomarker and therapeutic strategies targeting stathmin expression, phosphorylation, stability and protein interactions. We propose that stathmin activity is most likely to have clinical value as part of a composite taxane-response classifier that also incorporates intracellular drug exposure, tubulin isotypes and apoptotic competence.