Abstract 6864: Overcoming resistance to tubulin-targeting drugs with PM534: an innovative microtubule-targeting compound

Abstract Tubulin, a GTP-regulated protein essential for microtubule assembly, is a critical target in cancer therapy. However, current tubulin-targeting drugs face limitations due to toxicity and resistance mechanisms, associated with overexpression of either P-glycoprotein or β-III tubulin isotype. This study aimed to evaluate PM534, a novel compound targeting the colchicine-binding domain (CBD) on tubulin, for its potential to overcome these challenges. PM534´s transport properties were investigated applying MDR1-mediated transport assays in Abcb1KO-MDCKII cells. In vivo, PM534’s antitumor efficacy was assessed in athymic nude mice bearing xenografts of resistant tumors, including LoVo-Doxo cells with Pgp overexpression and HeLa βIII cells with β-III tubulin overexpression. Each xenograft group received a single intravenous (i.v.) dose of PM534 (5 mg/kg), and tumor growth was monitored over a 7-day period. The Km and Vmax kinetic parameters of human MDR1-mediated PM534 transport were determined to be 12.84 µM and 10.3 pmol/min/pmol transporter protein, respectively. In vivo data showed that PM534 significantly reduced tumor volumes in resistant models, achieving median tumor volumes of 131.4 mm3 in LoVo-Doxo xenografts and 163.4 mm3 in HeLa βIII xenografts by day 7, compared to placebo-treated controls (410.6 mm3 and 257.4 mm3, respectively). PM534’s efficacy surpassed paclitaxel in these resistant models, as its activity remained unaffected by Pgp overexpression or β-III tubulin presence—both common resistance mechanisms that limit other tubulin-targeting drugs. In conclusion, PM534 demonstrates potent antitumor activity in drug-resistant cancer models, effectively bypassing Pgp-mediated efflux and β-III tubulin-related resistance. These findings support PM534’s potential as a promising therapeutic candidate capable of overcoming the limitations of current tubulin-targeting agents in oncology. Citation Format: Maria José Guillen, Maria José Munoz, María Ángela Oliva, Daniel Torralba, Marcelo Lima Ribeiro, J. Fernando Díaz, Carmen Cuevas, Pablo M. Avilés. Overcoming resistance to tubulin-targeting drugs with PM534: an innovative microtubule-targeting compound [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6864.