Impaired DNA damage response pathways may create vulnerabilities of cancer cells that can be exploited therapeutically. One such selective vulnerability is the sensitivity of BRCA1- or BRCA2-defective tumors (hence defective in DNA repair by homologous recombination, HR) to inhibitors of the poly(ADP-ribose) polymerase-1 (PARP-1), an enzyme critical for repair pathways alternative to HR. While promising, treatment with PARP-1 inhibitors (PARP-1i) faces some hurdles, including (1) acquired resistance, (2) search for other sensitizing, non-BRCA1/2 cancer defects and (3) lack of biomarkers to predict response to PARP-1i. Here we addressed these issues using PARP-1i on 20 human cell lines from carcinomas of the breast, prostate, colon, pancreas and ovary. Aberrations of the Mre11-Rad50-Nbs1 (MRN) complex sensitized cancer cells to PARP-1i, while p53 status was less predictive, even in response to PARP-1i combinations with camptothecin or ionizing radiation. Furthermore, monitoring PARsylation and Rad51 foci formation as surrogate markers for PARP activity and HR, respectively, supported their candidacy for biomarkers of PARP-1i responses. As to resistance mechanisms, we confirmed the role of the multidrug resistance efflux transporters and its reversibility. More importantly, we demonstrated that shRNA lentivirus-mediated depletion of 53BP1 in human BRCA1-mutant breast cancer cells increased their resistance to PARP-1i. Given the preferential loss of 53BP1 in BRCA-defective and triple-negative breast carcinomas, our findings warrant assessment of 53BP1 among candidate predictive biomarkers of response to PARPi. Overall, this study helps characterize genetic and functional determinants of cellular responses to PARP-1i and contributes to the search for biomarkers to exploit PARP inhibitors in cancer therapy.
- MeSH
- antitumorózní látky farmakologie MeSH
- chemorezistence * MeSH
- DNA vazebné proteiny genetika metabolismus MeSH
- enzymy opravy DNA genetika metabolismus MeSH
- geny MDR MeSH
- inhibitory enzymů farmakologie MeSH
- intracelulární signální peptidy a proteiny * genetika MeSH
- kamptothecin farmakologie MeSH
- karcinom * farmakoterapie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- poškození DNA MeSH
- protein BRCA1 genetika metabolismus MeSH
- protein BRCA2 genetika MeSH
- proteiny buněčného cyklu genetika metabolismus MeSH
- regulace genové exprese u nádorů * MeSH
- záření gama terapeutické užití MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- MeSH
- androgenní receptory metabolismus MeSH
- cyklin-dependentní kinasy antagonisté a inhibitory MeSH
- inhibitory enzymů farmakologie MeSH
- lidé MeSH
- nádory prostaty metabolismus patologie MeSH
- nádory závislé na hormonech metabolismus patologie MeSH
- puriny farmakologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- MeSH
- buněčná smrt MeSH
- buněčné linie účinky léků účinky záření MeSH
- fluorescenční mikroskopie MeSH
- fotochemoterapie metody MeSH
- fotosenzibilizující látky farmakologie chemie MeSH
- lasery MeSH
- lidé MeSH
- metaloporfyriny farmakologie chemie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- techniky in vitro MeSH
