Title | Taxane resistance in prostate cancer is mediated by decreased drug-target engagement. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Gjyrezi 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 |
Journal | J Clin Invest |
Volume | 130 |
Issue | 6 |
Pagination | 3287-3298 |
Date Published | 2020 06 01 |
ISSN | 1558-8238 |
Keywords | Animals, 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. |
DOI | 10.1172/JCI132184 |
Alternate Journal | J Clin Invest |
PubMed ID | 32478682 |
PubMed Central ID | PMC7259995 |
Grant List | R01 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 |