ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells

Stephanie A. Yazinski; Valentine Comaills; Rémi Buisson; Marie Michelle Genois; Hai Dang Nguyen; Chu Kwen Ho; Tanya Todorova Kwan; Robert Morris; Sam Lauffer; André Nussenzweig; Sridhar Ramaswamy; Cyril H. Benes; Daniel A. Haber; Shyamala Maheswaran; Michael J. Birrer; Lee Zou

doi:10.1101/gad.290957.116

ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells

Stephanie A. Yazinski, Valentine Comaills, Rémi Buisson, Marie Michelle Genois, Hai Dang Nguyen, Chu Kwen Ho, Tanya Todorova Kwan, Robert Morris, Sam Lauffer, André Nussenzweig, Sridhar Ramaswamy, Cyril H. Benes, Daniel A. Haber, Shyamala Maheswaran, Michael J. Birrer, Lee Zou

Pharmacology

Research output: Contribution to journal › Article › peer-review

104 Scopus citations

Abstract

Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cells, but their efficacy in BRCA-deficient patients is limited by drug resistance. Here, we used derived cell lines and cells from patients to investigate how to overcome PARPi resistance. We found that the functions of BRCA1 in homologous recombination (HR) and replication fork protection are sequentially bypassed during the acquisition of PARPi resistance. Despite the lack of BRCA1, PARPi-resistant cells regain RAD51 loading to DNA double-stranded breaks (DSBs) and stalled replication forks, enabling two distinct mechanisms of PARPi resistance. Compared with BRCA1-proficient cells, PARPi-resistant BRCA1-deficient cells are increasingly dependent on ATR for survival. ATR inhibitors (ATRis) disrupt BRCA1-independent RAD51 loading to DSBs and stalled forks in PARPi-resistant BRCA1-deficient cells, overcoming both resistance mechanisms. In tumor cells derived from patients, ATRis also overcome the bypass of BRCA1/2 in fork protection. Thus, ATR inhibition is a unique strategy to overcome the PARPi resistance of BRCA-deficient cancers.

Original language	English (US)
Pages (from-to)	318-332
Number of pages	15
Journal	Genes and Development
Volume	31
Issue number	3
DOIs	https://doi.org/10.1101/gad.290957.116
State	Published - Feb 1 2017

Bibliographical note

Funding Information:
We thank S. Cantor, J. Chen, D. Durocher, N. Dyson, L. Ellisen, S. Orsulic, and B. Xia for reagents and discussions. This work was supported by grants from the National Institutes of Health (GM076388 and CA197779 to L.Z., and CA129933 to D.A.H.), National Cancer Institute Federal Share of Program Income (to L.Z.), Jim and Ann Orr MGH Research Scholar Award (to L.Z.), Susan Komen for the Cure (KG09042 to S.M.), and the Wellcome Trust (102696 to C.H.B.). The Flow Cytometry Core is supported by National Institutes of Health instrumentation grant 1S10RR023440-01A1. S.A.Y. was supported by a fellowship from the Department of Defense (W81XWH-13-1-0027). V.C. and R.B. have received support from the Philippe Foundation. M.-M.G. is a fellow of Fonds de recherche du Qu?bec-Sant?. H. D. N. was a Medical Discovery Post-doctoral Fellow. R.B. was a Marsha Rivkin Scholar. L.Z. is the James and Patricia Poitras Endowed Chair in Cancer Research.

Keywords

ATR
BRCA-deficient cancer
PARP inhibitor

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Yazinski, S. A., Comaills, V., Buisson, R., Genois, M. M., Nguyen, H. D., Ho, C. K., Kwan, T. T., Morris, R., Lauffer, S., Nussenzweig, A., Ramaswamy, S., Benes, C. H., Haber, D. A., Maheswaran, S., Birrer, M. J., & Zou, L. (2017). ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells. Genes and Development, 31(3), 318-332. https://doi.org/10.1101/gad.290957.116

ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells. / Yazinski, Stephanie A.; Comaills, Valentine; Buisson, Rémi; Genois, Marie Michelle; Nguyen, Hai Dang; Ho, Chu Kwen; Kwan, Tanya Todorova; Morris, Robert; Lauffer, Sam; Nussenzweig, André; Ramaswamy, Sridhar; Benes, Cyril H.; Haber, Daniel A.; Maheswaran, Shyamala; Birrer, Michael J.; Zou, Lee.

In: Genes and Development, Vol. 31, No. 3, 01.02.2017, p. 318-332.

Research output: Contribution to journal › Article › peer-review

Yazinski, SA, Comaills, V, Buisson, R, Genois, MM, Nguyen, HD, Ho, CK, Kwan, TT, Morris, R, Lauffer, S, Nussenzweig, A, Ramaswamy, S, Benes, CH, Haber, DA, Maheswaran, S, Birrer, MJ & Zou, L 2017, 'ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells', Genes and Development, vol. 31, no. 3, pp. 318-332. https://doi.org/10.1101/gad.290957.116

Yazinski, Stephanie A. ; Comaills, Valentine ; Buisson, Rémi ; Genois, Marie Michelle ; Nguyen, Hai Dang ; Ho, Chu Kwen ; Kwan, Tanya Todorova ; Morris, Robert ; Lauffer, Sam ; Nussenzweig, André ; Ramaswamy, Sridhar ; Benes, Cyril H. ; Haber, Daniel A. ; Maheswaran, Shyamala ; Birrer, Michael J. ; Zou, Lee. / ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells. In: Genes and Development. 2017 ; Vol. 31, No. 3. pp. 318-332.

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abstract = "Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cells, but their efficacy in BRCA-deficient patients is limited by drug resistance. Here, we used derived cell lines and cells from patients to investigate how to overcome PARPi resistance. We found that the functions of BRCA1 in homologous recombination (HR) and replication fork protection are sequentially bypassed during the acquisition of PARPi resistance. Despite the lack of BRCA1, PARPi-resistant cells regain RAD51 loading to DNA double-stranded breaks (DSBs) and stalled replication forks, enabling two distinct mechanisms of PARPi resistance. Compared with BRCA1-proficient cells, PARPi-resistant BRCA1-deficient cells are increasingly dependent on ATR for survival. ATR inhibitors (ATRis) disrupt BRCA1-independent RAD51 loading to DSBs and stalled forks in PARPi-resistant BRCA1-deficient cells, overcoming both resistance mechanisms. In tumor cells derived from patients, ATRis also overcome the bypass of BRCA1/2 in fork protection. Thus, ATR inhibition is a unique strategy to overcome the PARPi resistance of BRCA-deficient cancers.",

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note = "Funding Information: We thank S. Cantor, J. Chen, D. Durocher, N. Dyson, L. Ellisen, S. Orsulic, and B. Xia for reagents and discussions. This work was supported by grants from the National Institutes of Health (GM076388 and CA197779 to L.Z., and CA129933 to D.A.H.), National Cancer Institute Federal Share of Program Income (to L.Z.), Jim and Ann Orr MGH Research Scholar Award (to L.Z.), Susan Komen for the Cure (KG09042 to S.M.), and the Wellcome Trust (102696 to C.H.B.). The Flow Cytometry Core is supported by National Institutes of Health instrumentation grant 1S10RR023440-01A1. S.A.Y. was supported by a fellowship from the Department of Defense (W81XWH-13-1-0027). V.C. and R.B. have received support from the Philippe Foundation. M.-M.G. is a fellow of Fonds de recherche du Qu?bec-Sant?. H. D. N. was a Medical Discovery Post-doctoral Fellow. R.B. was a Marsha Rivkin Scholar. L.Z. is the James and Patricia Poitras Endowed Chair in Cancer Research.",

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AU - Yazinski, Stephanie A.

AU - Comaills, Valentine

AU - Buisson, Rémi

AU - Genois, Marie Michelle

AU - Nguyen, Hai Dang

AU - Ho, Chu Kwen

AU - Kwan, Tanya Todorova

AU - Morris, Robert

AU - Lauffer, Sam

AU - Nussenzweig, André

AU - Ramaswamy, Sridhar

AU - Benes, Cyril H.

AU - Haber, Daniel A.

AU - Maheswaran, Shyamala

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AU - Zou, Lee

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N2 - Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cells, but their efficacy in BRCA-deficient patients is limited by drug resistance. Here, we used derived cell lines and cells from patients to investigate how to overcome PARPi resistance. We found that the functions of BRCA1 in homologous recombination (HR) and replication fork protection are sequentially bypassed during the acquisition of PARPi resistance. Despite the lack of BRCA1, PARPi-resistant cells regain RAD51 loading to DNA double-stranded breaks (DSBs) and stalled replication forks, enabling two distinct mechanisms of PARPi resistance. Compared with BRCA1-proficient cells, PARPi-resistant BRCA1-deficient cells are increasingly dependent on ATR for survival. ATR inhibitors (ATRis) disrupt BRCA1-independent RAD51 loading to DSBs and stalled forks in PARPi-resistant BRCA1-deficient cells, overcoming both resistance mechanisms. In tumor cells derived from patients, ATRis also overcome the bypass of BRCA1/2 in fork protection. Thus, ATR inhibition is a unique strategy to overcome the PARPi resistance of BRCA-deficient cancers.

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