CLIP-170S is a microtubule +TIP variant that confers resistance to taxanes by impairing drug-target engagement

73 p.-5 fig.-1 tab.-11 fig supl.-2 vid. supl.Taxanes are widely used cancer chemotherapeutics. However, intrinsic resistance limits their efficacy without any actionable resistance mechanism. We have discovered a microtubule (MT) plus-end-binding CLIP-170 protein variant, hereafter CLIP-170S, which we found enriched in taxane-resistant cell lines and patient samples. CLIP-170S lacks the first Cap-Gly motif, forms longer comets, and impairs taxane access to its MT luminal binding site. CLIP-170S knockdown reversed taxane resistance in cells and xenografts, whereas its re-expression led to resistance, suggesting causation. Using a computational approach in conjunction with the connectivity map, we unexpectedly discovered that Imatinib was predicted to reverse CLIP-170S-mediated taxane resistance. Indeed, Imatinib treatment selectively depleted CLIP-170S, thus completely reversing taxane resistance. Other RTK inhibitors also depleted CLIP-170S, suggesting a class effect. Herein, we identify CLIP-170S as a clinically prevalent variant that confers taxane resistance, whereas the discovery of Imatinib as a CLIP-170S inhibitor provides novel therapeutic opportunities for future trials.This work was supported in part by the NIH T32 training grant 5T32CA062948 (to K.K.), the NIH T32 training grant 5T32CA062948 (to G.G.), the NIH T32 training grant 5T32CA203702 (to U.D.C.) by Clinical and Translational Science Center at Weill Cornell Medicine NIH/NCATS grant ULTR00457 (to G.G.), the NIH/NCI R01CA228512 (to P.G., M.A.S., and O.E.), NIH/NCI R21 CA216800 (to P.G.), NIH/NCI R01 CA179100 (to P.G.), DoD PC180637 (P.G., A.R.C.), and by the Ministerio de Economía y Competitividad grant BFU2016-75319-R and European Union H2020-MSCA-ITN-ETN/0582 ITN TUBINTRAIN (awarded to J.F.D.). D.S. was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. Y.L. and M.A.S. were supported, in part, by funds from the Clinical and Translational Science Center (CTSC), National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health, award # UL1-TR002384-01.Peer reviewe