Back to Search
Start Over
Enhancing Abiraterone Acetate Efficacy in Androgen Receptor-positive Triple-negative Breast Cancer: Chk1 as a Potential Target.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2019 Jan 15; Vol. 25 (2), pp. 856-867. Date of Electronic Publication: 2018 Oct 23. - Publication Year :
- 2019
-
Abstract
- Purpose: Our aim was to identify predictive factors of abiraterone acetate efficacy and putative new druggable targets in androgen receptor (AR)-positive triple-negative breast cancer (TNBC) treated in the UCBG 2012-1 trial. Experimental Design: We defined abiraterone acetate response as either complete or partial response, or stable disease at 6 months. We sequenced 91 general and breast cancer-associated genes from the tumor DNA samples. We analyzed transcriptomes from the extracted RNA samples on a NanoString platform and performed IHC using tissue microarrays. We assessed abiraterone acetate and Chk1 inhibitors (GDC-0575 and AZD7762) efficacies, either alone or in combination, on cell lines grown in vitro and in vivo .<br />Results: Classic IHC apocrine markers including AR, FOXA1, GGT1, and GCDFP15, from patients' tumors allowed identifying abiraterone acetate-responders and nonresponders. All responders had clear apocrine features. Transcriptome analysis revealed that 31 genes were differentially expressed in the two subgroups, 9 of them being linked to proliferation and DNA damage repair. One of the most significant differences was the overexpression, in nonresponders, of CHEK1 , a gene encoding Chk1, a protein kinase that can be blocked by specific inhibitors. On the basis of cell line experiments, abiraterone acetate and Chk1 inhibitor combination showed at least additive effect on cell viability, cell cycle, apoptosis, and accumulation of DNA damages. In vivo , orthotopic xenograft experiments confirmed the efficacy of this combination therapy.<br />Conclusions: This study suggests that apocrine features can be helpful in the identification of abiraterone acetate-responders. We identified Chk1 as a putative drug target in AR-positive TNBCs.<br /> (©2018 American Association for Cancer Research.)
- Subjects :
- Abiraterone Acetate therapeutic use
Aged
Aged, 80 and over
Animals
Antineoplastic Agents therapeutic use
Apoptosis drug effects
Biomarkers, Tumor
Cell Cycle drug effects
Cell Line, Tumor
Cell Survival drug effects
Checkpoint Kinase 1 antagonists & inhibitors
Checkpoint Kinase 1 metabolism
Disease Models, Animal
Female
High-Throughput Nucleotide Sequencing
Humans
Immunohistochemistry
Mice
Middle Aged
Neoplasm Grading
Neoplasm Staging
Protein Kinase Inhibitors pharmacology
Triple Negative Breast Neoplasms drug therapy
Triple Negative Breast Neoplasms pathology
Xenograft Model Antitumor Assays
Abiraterone Acetate pharmacology
Antineoplastic Agents pharmacology
Receptors, Androgen metabolism
Triple Negative Breast Neoplasms metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 25
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 30352905
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-18-1469