TY - JOUR

T1 - Evaluation of candidate biomarkers to predict cancer cell sensitivity or resistance to PARP-1 inhibitor treatment

AU - Oplustilova, L.

AU - Wolanin, K.

AU - Bartkova, J.

AU - Lukas, J.

AU - Bartek, J.

AU - Lau, Allan

AU - O'Connor, M.J.

AU - Mistrik, M.

AU - Korinkova, G.

AU - Simkova, D.

AU - Bouchal, J.

AU - Lenobel, R.

PY - 2012/10/15

Y1 - 2012/10/15

N2 - 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 confrmed the role of the multidrug resistance efux 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 fndings 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.

AB - 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 confrmed the role of the multidrug resistance efux 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 fndings 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.

UR - http://www.scopus.com/inward/record.url?scp=84868015370&partnerID=8YFLogxK

U2 - 10.4161/cc.22026

DO - 10.4161/cc.22026

M3 - Journal article

C2 - 22983061

AN - SCOPUS:84868015370

VL - 11

SP - 3837

EP - 3850

JO - Cell Cycle

JF - Cell Cycle

SN - 1538-4101

IS - 20

ER -