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.

• Authors: Giuseppe Galletti, Chao Zhang, Ada Gjyrezi, Kyle Cleveland, Jiaren Zhang, Sarah Powell, Prashant V Thakkar, Doron Betel, Manish A Shah, Paraskevi Giannakakou
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 14 Pg. 3771-3783 (07 15 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 32321717 (Publication Type: Clinical Trial, Phase II, Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Tubulin
• Docetaxel
• Kinesins
• Cisplatin
• Fluorouracil

Topics

• Adult
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Biopsy
• Cell Line, Tumor
• Cisplatin (pharmacology, therapeutic use)
• Docetaxel (pharmacology, therapeutic use)
• Drug Resistance, Neoplasm
• Female
• Fluorouracil (pharmacology, therapeutic use)
• Gastric Mucosa (drug effects, pathology)
• Humans
• Kaplan-Meier Estimate
• Kinesins (metabolism)
• Male
• Microtubules (drug effects, metabolism)
• Middle Aged
• Pilot Projects
• Progression-Free Survival
• Stomach Neoplasms (drug therapy, mortality, pathology)
• Tubulin (metabolism)