Abstract 2623: Variants of CLIP-170 associated with taxane resistance in tumors

Despite its widespread use, the majority of patients with gastric cancer (GC) will not respond to taxane chemotherapy due to resistance mechanisms. Recently, we reported the discovery of a novel truncated variant of the microtubule plus-end binding protein CLIP-170, hereafter CLIP-170S, whose expression is enriched in taxane resistant cell lines and patients with GC. Mass-spec proteomics and 5’-RACE further showed that CLIP-170S lacked the first 155 amino acids, including the Cap-Gly motif required for microtubule plus-end localization. CLIP-170S knockdown reversed taxane resistance in cells and xenografts, whereas its re-expression led to resistance, suggesting causation. Unlike canonical CLIP-170, we showed that CLIP-170S was mislocalized from the MT plus-end to the MT lattice. Computational analysis of RNA-seq data in conjunction with the connectivity map from taxane-sensitive and resistant GC cell lines, predicted imatinib as the top candidate drug to overcome drug resistance. Imatinib treatment completely reversed taxane resistance, as predicted, and did so unexpectedly by selective depletion of CLIP-170S. Other RTK inhibitors also depleted CLIP-170S, suggesting a class effect. We are currently unraveling the molecular mechanisms by which a) CLIP-170S impairs taxane association to its microtubule binding site and b) Imatinib and other RTK inhibitors selectively deplete CLIP-170S. Our data show that CLIP-170S is a clinically prevalent variant that confers taxane resistance in tumors, whereas the discovery of Imatinib as a CLIP-170S inhibitor provides novel therapeutic opportunities for future trials. Citation Format: Prashant V. Thakkar, Katsuhiro Kita, Urko del Castillo, William G. Stone, Giuseppe Galletti, Neel Madhukar, Elena Vila Navarro, Elena Barasoain, Holly V. Goodson, Dan Sackett, José Fernando Díaz, Yao Lu, Arindam RoyChoudhury, Henrik Molina, Olivier Elemento, Manish A. Shah, Paraskevi Giannakakou. Variants of CLIP-170 associated with taxane resistance in tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2623.