Cisplatin resistance in an ovarian cancer model is mediated by microtubule dynamics regulator TPPP3 in synergy with tubulin code rewiring

Summary Cisplatin is a mainstay in cancer treatment, but toxicity and resistance limit its potential. Using RNA sequencing (RNA-seq), we show that ovarian cancer cells undergo broad changes in the microtubule cytoskeleton that correlate with resistance. Consistent with this, we find that cisplatin directly impacts microtubule dynamics in vitro and in cells. Paclitaxel counteracts cisplatin and increases resistance. By purifying tubulin from cisplatin-sensitive, -resistant, and -re-sensitized ovarian cancer cells, we demonstrate that resistance acquisition rewires the tubulin code, leading to microtubule stabilization. Furthermore, tubulin polymerization-promoting protein 3 (TPPP3) contributes to resistance. In vitro, TPPP3 synergizes with tubulin isotypes from resistant cells to yield maximal microtubule stabilization in response to cisplatin. Database analysis shows that patients with low TPPP3 levels have improved therapeutic outcome. Our findings implicate TPPP3 and microtubule dysregulation in cisplatin resistance, independent of effects through DNA damage, and have bearing on the etiology of cisplatin-associated neuropathies and ototoxicity.