Pharmacological screening and transcriptomic functional analyses identify a synergistic interaction between dasatinib and olaparib in triple‐negative breast cancer

Identification of druggable vulnerabilities is a main objective in triple‐negative breast cancer (TNBC), where no curative therapies exist. Gene set enrichment analyses (GSEA) and a pharmacological evaluation using a library of compounds were used to select potential druggable combinations. MTT and...

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Bibliographic Details
Published in:Journal of cellular and molecular medicine 2020-03, Vol.24 (5), p.3117-3127
Main Authors: Corrales‐Sánchez, Verónica, Noblejas‐López, María del Mar, Nieto‐Jiménez, Cristina, Pérez‐Peña, Javier, Montero, Juan Carlos, Burgos, Miguel, Galán‐Moya, Eva M., Pandiella, Atanasio, Ocaña, Alberto
Format: Article
Language:English
Subjects:
Apoptosis
Breast cancer
Caspase
Cell culture
Cell cycle
Cell Line, Tumor
Cell Proliferation - drug effects
Colorectal cancer
dasatinib
Dasatinib - pharmacology
Deoxyribonucleic acid
DNA
DNA damage
DNA repair
Drug dosages
Drug Evaluation, Preclinical
Drug Resistance, Neoplasm - genetics
Drug Synergism
Female
Flow cytometry
Genes
Humans
Mutation
olaparib
Original
Ovarian cancer
Phthalazines - pharmacology
Piperazines - pharmacology
Poly(ADP-ribose) Polymerase Inhibitors - pharmacology
Prostate cancer
Protein Kinase Inhibitors - pharmacology
Regulatory approval
screening
Software
Solid tumors
Transcriptome - drug effects
triple negative
Triple Negative Breast Neoplasms - drug therapy
Triple Negative Breast Neoplasms - genetics
Triple Negative Breast Neoplasms - pathology
Tumors
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Summary:Identification of druggable vulnerabilities is a main objective in triple‐negative breast cancer (TNBC), where no curative therapies exist. Gene set enrichment analyses (GSEA) and a pharmacological evaluation using a library of compounds were used to select potential druggable combinations. MTT and studies with semi‐solid media were performed to explore the activity of the combinations. TNBC cell lines (MDAMB‐231, BT549, HS‐578T and HCC3153) and an additional panel of 16 cell lines were used to assess the activity of the two compounds. Flow cytometry experiments and biochemical studies were also performed to explore the mechanism of action. GSEA were performed using several data sets (GSE21422, GSE26910, GSE3744, GSE65194 and GSE42568), and more than 35 compounds against the identified functions were evaluated to discover druggable opportunities. Analyses done with the Chou and Talalay algorithm confirmed the synergy of dasatinib and olaparib. The combination of both agents significantly induced apoptosis in a caspase‐dependent manner and revealed a pleotropic effect on cell cycle: Dasatinib arrested cells in G0/G1 and olaparib in G2/M. Dasatinib inhibited pChk1 and induced DNA damage measured by pH2AX, and olaparib increased pH3. Finally, the effect of the combination was also evaluated in a panel of 18 cell lines representative of the most frequent solid tumours, observing a particularly synergism in ovarian cancer. Breast cancer, triple negative, dasatinib, olaparib, screening.
ISSN:1582-1838
1582-4934
DOI:10.1111/jcmm.14980