Taxane resistance in prostate cancer is mediated by decreased drug-target engagement.

TitleTaxane resistance in prostate cancer is mediated by decreased drug-target engagement.
Publication TypeJournal Article
Year of Publication2020
AuthorsGjyrezi A, Xie F, Voznesensky O, Khanna P, Calagua C, Bai Y, Kung J, Wu J, Corey E, Montgomery B, Mace S, Gianolio DA, Bubley GJ, Balk SP, Giannakakou P, Bhatt RS
JournalJ Clin Invest
Volume130
Issue6
Pagination3287-3298
Date Published2020 06 01
ISSN1558-8238
KeywordsAnimals, Bridged-Ring Compounds, Cell Line, Tumor, Docetaxel, Drug Resistance, Neoplasm, Humans, Male, Mice, Mice, Nude, Microtubules, Prostatic Neoplasms, Taxoids
Abstract

Despite widespread use of taxanes, mechanisms of action and resistance in vivo remain to be established, and there is no way of predicting who will respond to therapy. This study examined prostate cancer (PCa) xenografts and patient samples to identify in vivo mechanisms of taxane action and resistance. Docetaxel drug-target engagement was assessed by confocal anti-tubulin immunofluorescence to quantify microtubule bundling in interphase cells and aberrant mitoses. Tumor biopsies from metastatic PCa patients obtained 2 to 5 days after their first dose of docetaxel or cabazitaxel were processed to assess microtubule bundling, which correlated with clinical response. Microtubule bundling was evident in PCa xenografts 2 to 3 days after docetaxel treatment but was decreased or lost with acquired resistance. Biopsies after treatment with leuprolide plus docetaxel showed extensive microtubule bundling as did biopsies obtained 2 to 3 days after initiation of docetaxel or cabazitaxel in 2 patients with castration-resistant PCa with clinical responses. In contrast, microtubule bundling in biopsies 2 to 3 days after the first dose of docetaxel was markedly lower in 4 nonresponding patients. These findings indicate that taxanes target both mitotic and interphase cells in vivo and that resistance is through mechanisms that impair drug-target engagement. Moreover, the findings suggest that microtubule bundling after initial taxane treatment may be a predictive biomarker for clinical response.

DOI10.1172/JCI132184
Alternate JournalJ Clin Invest
PubMed ID32478682
PubMed Central IDPMC7259995
Grant ListR01 CA177165 / CA / NCI NIH HHS / United States
R21 CA216800 / CA / NCI NIH HHS / United States
R01 CA196996 / CA / NCI NIH HHS / United States
P01 CA163227 / CA / NCI NIH HHS / United States
P50 CA090381 / CA / NCI NIH HHS / United States
R01 CA179100 / CA / NCI NIH HHS / United States
P50 CA211024 / CA / NCI NIH HHS / United States