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Statements

Subject Item
n2:RIV%2F61989592%3A15310%2F12%3A33140157%21RIV13-MSM-15310___
rdf:type
n9:Vysledek skos:Concept
dcterms:description
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. 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.
dcterms:title
Evaluation of candidate biomarkers to predict cancer cell sensitivity or resistance to PARP-1 inhibitor treatment Evaluation of candidate biomarkers to predict cancer cell sensitivity or resistance to PARP-1 inhibitor treatment
skos:prefLabel
Evaluation of candidate biomarkers to predict cancer cell sensitivity or resistance to PARP-1 inhibitor treatment Evaluation of candidate biomarkers to predict cancer cell sensitivity or resistance to PARP-1 inhibitor treatment
skos:notation
RIV/61989592:15310/12:33140157!RIV13-MSM-15310___
n9:predkladatel
n19:orjk%3A15310
n3:aktivita
n10:P
n3:aktivity
P(ED0030/01/01), P(NS10282)
n3:cisloPeriodika
20
n3:dodaniDat
n17:2013
n3:domaciTvurceVysledku
n18:9896821
n3:druhVysledku
n11:J
n3:duvernostUdaju
n5:S
n3:entitaPredkladatele
n12:predkladatel
n3:idSjednocenehoVysledku
135064
n3:idVysledku
RIV/61989592:15310/12:33140157
n3:jazykVysledku
n15:eng
n3:klicovaSlova
MRE11; MAMMARY-TUMORS; TUMOR-SUPPRESSOR; SYNTHETIC LETHALITY; HOMOLOGOUS RECOMBINATION; IN-VITRO ASSAYS; STRAND BREAK REPAIR; ADP-RIBOSE POLYMERASE; POLY(ADP-RIBOSE) POLYMERASE INHIBITION; DNA-DAMAGE RESPONSE
n3:klicoveSlovo
n4:HOMOLOGOUS%20RECOMBINATION n4:POLY%28ADP-RIBOSE%29%20POLYMERASE%20INHIBITION n4:IN-VITRO%20ASSAYS n4:ADP-RIBOSE%20POLYMERASE n4:DNA-DAMAGE%20RESPONSE n4:SYNTHETIC%20LETHALITY n4:MRE11 n4:STRAND%20BREAK%20REPAIR n4:TUMOR-SUPPRESSOR n4:MAMMARY-TUMORS
n3:kodStatuVydavatele
US - Spojené státy americké
n3:kontrolniKodProRIV
[4F922B13C0FA]
n3:nazevZdroje
Cell cycle
n3:obor
n6:FD
n3:pocetDomacichTvurcuVysledku
1
n3:pocetTvurcuVysledku
12
n3:projekt
n8:ED0030%2F01%2F01 n8:NS10282
n3:rokUplatneniVysledku
n17:2012
n3:svazekPeriodika
11
n3:tvurceVysledku
Lukas, J. O&Apos Wolanin, K. Mistrík, Martin Bartkova, J. Connor, M. Oplustilova, L. Lau, A. Bouchal, Jan Kořínková, Gabriela Šimková, Dana Lenobel, René Bártek, Jiří
n3:wos
000309814300025
s:issn
1538-4101
s:numberOfPages
14
n13:doi
10.4161/cc.22026
n14:organizacniJednotka
15310