Manish A Shah 1,2 , Paraskevi Giannakakou 3,2 , Giuseppe Galletti 1,2 , Chao Zhang 4 , Ada Gjyrezi 1,2 , Kyle Cleveland 1,2 , Jiaren Zhang 1,2 , Sarah Powell 1,2 , Prashant V Thakkar 1,2 , Doron Betel 1,4 Show Affiliations »
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. ©2020 American Association for Cancer Research.
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 . ©2020 American Association for Cancer Research.
Entities: CellLine
Chemical
Disease
Gene
Species
Year: 2020
PMID： 32321717 DOI： 10.1158/1078-0432.CCR-19-3018
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531