Back to Search
Start Over
Three dimensional primary cultures for selecting human breast cancers that are sensitive to the anti-tumor activity of ipatasertib or taselisib in combination with anti-microtubule cytotoxic drugs
- Source :
- Breast (Edinburgh, Scotland). 41
- Publication Year :
- 2018
-
Abstract
- Two inhibitors of phosphatidylinositol 3-kinase (PI3K) pathway taselisib, targeting the mutant PI3K-subunit-alpha (PI3KA) and ipatasertib, AKT-inhibitor, are currently under clinical investigation in breast cancer (BC) patients. We have previously demonstrated the anti-tumor efficacy of these anti-PI3K/AKT-inibitors in combination with anti-microtubule drugs in human BC cell lines, through a complete cytoskeleton disorganization. In this work, we generated ex-vivo three-dimensional (3D) cultures from human BC as a model to test drug efficacy and to identify new molecular biomarkers for selection of BC patients suitable for anti-PI3K/AKT-inibitors treatment. We have established 3D cultures from 25/27 human BC samples, in which the ability of growth in vitro replicates the clinical and biological aggressiveness of the original tumors. According to the results of next generation sequencing analysis, a direct correlation was found between PI3KA mutations and the sensitivity in 3D models in vitro to taselisib and ipatasertib alone and combined with anti-microtubule agents. Moreover, mutations in HER and MAPK families related genes, including EGFR, KRAS and BRAF, were found in resistant samples, suggesting their potential role as negative predictive factors of response to these agents. Thus, we demonstrated that ex vivo 3D cultures from human BC patients allow a rapid and efficient drug screening for chemotherapies and targeted agents in genetically selected patients and represent an innovative model to identify new biomarkers of drug resistance.
- Subjects :
- 0301 basic medicine
Drug
media_common.quotation_subject
Cell Culture Techniques
Antineoplastic Agents
Breast Neoplasms
Drug resistance
medicine.disease_cause
Ipatasertib
Piperazines
03 medical and health sciences
0302 clinical medicine
Breast cancer
Cell Line, Tumor
Medicine
Humans
PI3K/AKT/mTOR pathway
media_common
Mutation
business.industry
Taselisib
AKT
Imidazoles
High-Throughput Nucleotide Sequencing
General Medicine
medicine.disease
Tubulin Modulators
Oxazepines
030104 developmental biology
Pyrimidines
Cell culture
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Three-dimensional cell culture
Cancer research
Surgery
Female
KRAS
business
Ex vivo model
Subjects
Details
- ISSN :
- 15323080
- Volume :
- 41
- Database :
- OpenAIRE
- Journal :
- Breast (Edinburgh, Scotland)
- Accession number :
- edsair.doi.dedup.....f864c9089263ff3b58e8fcebd24b02e0