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

Overview

abstract

  • 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.

publication date

  • October 20, 2021

Research

keywords

  • Drug Resistance, Neoplasm
  • Gene Deletion
  • Imatinib Mesylate
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • Neoplasm Recurrence, Local
  • Stomach Neoplasms
  • Taxoids

Identity

PubMed Central ID

  • PMC8665049

Scopus Document Identifier

  • 85120173651

Digital Object Identifier (DOI)

  • 10.1016/j.canlet.2007.07.022

PubMed ID

  • 34672971

Additional Document Info

volume

  • 56

issue

  • 23