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

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.

Automated summary

Taxanes are widely used cancer chemotherapeutics, but intrinsic resistance can limit their efficacy. A microtubule (MT) variant called CLIP-170S was found to be enriched in taxane-resistant samples, and its depletion reversed resistance. Imatinib was unexpectedly discovered to reverse CLIP-170S-mediated resistance, providing a novel therapeutic opportunity for future trials.