Microtubule Engagement with Taxane Is Altered in Taxane-Resistant Gastric Cancer

Abstract

Purpose: Although taxane-based therapy is standard treatment for advanced gastric cancer, a majority of patients exhibit intrinsic resistance to taxanes. Here, we aim to identify the molecular basis of taxane resistance in gastric cancer. Experimental Design: We performed a post hoc analysis of the TAX-325 clinical trial and molecular interrogation of gastric cancer cell lines to assess the benefit of docetaxel in diffuse (DIF-GC) versus intestinal (INT-GC) gastric cancer. We assessed drug-induced microtubule stabilization in gastric cancer cells and in biopsies of patients with gastric cancer treated with taxanes. We performed transcriptome analysis in taxane-treated gastric cancer cells and patients to identify molecular drivers of taxane resistance. Results: Patients with DIF-GC did not derive a clinical benefit from taxane treatment suggesting intrinsic taxane resistance. DIF-GC cell lines displayed intrinsic resistance specific to taxanes because of impaired drug-induced microtubule stabilization, in the absence of tubulin mutations or decreased drug accumulation. Using taxane-treated gastric cancer patient biopsies, we demonstrated that absence of drug–target engagement was correlated with clinical taxane resistance. Taxane-sensitive cell lines displayed faster microtubule dynamics at baseline, implicating proteins that regulate cytoskeletal dynamics in intrinsic taxane resistance. Differential gene expression analysis of untreated and docetaxel-treated gastric cancer lines and patient samples identified kinesins to be associated with taxane sensitivity in vitro and in patient samples. Conclusions: Our data reveal that taxane resistance is more prevalent in patients with DIF-GC, support assessment of drug–target engagement as an early read-out of taxane clinical efficacy, and encourage the investigation of kinesins and other microtubule-associated proteins as potentially targetable mediators of taxane resistance in gastric cancer.