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BRCA2 reversion mutation–independent resistance to PARP inhibition through impaired DNA prereplication complex function.

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Title: BRCA2 reversion mutation–independent resistance to PARP inhibition through impaired DNA prereplication complex function.
Authors: Pappas, Kyrie1, Ferrari, Matteo2, Smith, Perianne3, Nandakumar, Subhiksha4,5, Khan, Zahra1, Young, Serina B.6, LaClair, Justin7, Vincenzo Russo, Marco8, Huang-Hobbs, Emmet1, Schultz, Nikolaus1,4,5, Abida, Wassim9, Karthaus, Wouter10, Jasin, Maria2, Sawyers, Charles L.1,11 sawyersc@mskcc.org
Source: Proceedings of the National Academy of Sciences of the United States of America. 6/10/2025, Vol. 122 Issue 23, p1-10. 21p.
Subjects: Adenosine diphosphate ribose, Castration-resistant prostate cancer, Homologous recombination, Replication fork, Cell cycle proteins
Abstract: Recent approvals of polymeric adenosine diphosphate ribose (poly(ADP-ribose) polymerase inhibitors (PARPi) for BRCA-mutant metastatic castration resistant prostate cancer necessitate an understanding of the factors that shape sensitivity and resistance. Reversion mutations that restore homologous recombination (HR) repair are detected in ~50 to 80% of BRCA-mutant patients who respond but subsequently relapse, but there is currently little insight into why only ~50% of BRCA-mutant patients display upfront resistance. To address this question, we performed a genome-wide CRISPR screen to identify genomic determinants of PARPi resistance in murine Brca2Δ/Δ prostate organoids genetically engineered in a manner that precludes the development of reversion mutations. Remarkably, we recovered multiple independent single guide RNAs (sgRNAs) targeting three different members (Cdt1, Cdc6, and Dbf4) of the DNA prereplication complex (pre-RC), each of which independently conferred resistance to olaparib and the next-generation PARP-1 selective inhibitor AZD5305. Moreover, sensitivity to PARP inhibition was restored in Brca2Δ/Δ, Cdc6-depleted prostate cells by knockdown of geminin, a negative regulator of Cdt1, further implicating the critical role of a functional pre-RC complex in PARPi sensitivity. Furthermore, ~50% of CRPC tumors have copy number loss of pre-RC complex genes, particularly CDT1. Mechanistically, prostate cells with impaired pre-RC activity displayed rapid resolution of olaparib-induced DNA damage as well as protection from replication fork degradation caused by Brca2 loss, providing insight into how Brca2-mutant cancer cells can escape cell death from replication stress induced by PARP inhibition in the absence of HR repair. Of note, a pharmacologic inhibitor that targets the CDT1/geminin complex (AF615) restored sensitivity to AZD5305, providing a potential translational avenue to enhance sensitivity to PARP inhibition. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: BRCA2 reversion mutation–independent resistance to PARP inhibition through impaired DNA prereplication complex function.
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  Data: <searchLink fieldCode="AR" term="%22Pappas%2C+Kyrie%22">Pappas, Kyrie</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Ferrari%2C+Matteo%22">Ferrari, Matteo</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Smith%2C+Perianne%22">Smith, Perianne</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Nandakumar%2C+Subhiksha%22">Nandakumar, Subhiksha</searchLink><relatesTo>4,5</relatesTo><br /><searchLink fieldCode="AR" term="%22Khan%2C+Zahra%22">Khan, Zahra</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Young%2C+Serina+B%2E%22">Young, Serina B.</searchLink><relatesTo>6</relatesTo><br /><searchLink fieldCode="AR" term="%22LaClair%2C+Justin%22">LaClair, Justin</searchLink><relatesTo>7</relatesTo><br /><searchLink fieldCode="AR" term="%22Vincenzo+Russo%2C+Marco%22">Vincenzo Russo, Marco</searchLink><relatesTo>8</relatesTo><br /><searchLink fieldCode="AR" term="%22Huang-Hobbs%2C+Emmet%22">Huang-Hobbs, Emmet</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Schultz%2C+Nikolaus%22">Schultz, Nikolaus</searchLink><relatesTo>1,4,5</relatesTo><br /><searchLink fieldCode="AR" term="%22Abida%2C+Wassim%22">Abida, Wassim</searchLink><relatesTo>9</relatesTo><br /><searchLink fieldCode="AR" term="%22Karthaus%2C+Wouter%22">Karthaus, Wouter</searchLink><relatesTo>10</relatesTo><br /><searchLink fieldCode="AR" term="%22Jasin%2C+Maria%22">Jasin, Maria</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Sawyers%2C+Charles+L%2E%22">Sawyers, Charles L.</searchLink><relatesTo>1,11</relatesTo><i> sawyersc@mskcc.org</i>
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  Data: Recent approvals of polymeric adenosine diphosphate ribose (poly(ADP-ribose) polymerase inhibitors (PARPi) for BRCA-mutant metastatic castration resistant prostate cancer necessitate an understanding of the factors that shape sensitivity and resistance. Reversion mutations that restore homologous recombination (HR) repair are detected in ~50 to 80% of BRCA-mutant patients who respond but subsequently relapse, but there is currently little insight into why only ~50% of BRCA-mutant patients display upfront resistance. To address this question, we performed a genome-wide CRISPR screen to identify genomic determinants of PARPi resistance in murine Brca2Δ/Δ prostate organoids genetically engineered in a manner that precludes the development of reversion mutations. Remarkably, we recovered multiple independent single guide RNAs (sgRNAs) targeting three different members (Cdt1, Cdc6, and Dbf4) of the DNA prereplication complex (pre-RC), each of which independently conferred resistance to olaparib and the next-generation PARP-1 selective inhibitor AZD5305. Moreover, sensitivity to PARP inhibition was restored in Brca2Δ/Δ, Cdc6-depleted prostate cells by knockdown of geminin, a negative regulator of Cdt1, further implicating the critical role of a functional pre-RC complex in PARPi sensitivity. Furthermore, ~50% of CRPC tumors have copy number loss of pre-RC complex genes, particularly CDT1. Mechanistically, prostate cells with impaired pre-RC activity displayed rapid resolution of olaparib-induced DNA damage as well as protection from replication fork degradation caused by Brca2 loss, providing insight into how Brca2-mutant cancer cells can escape cell death from replication stress induced by PARP inhibition in the absence of HR repair. Of note, a pharmacologic inhibitor that targets the CDT1/geminin complex (AF615) restored sensitivity to AZD5305, providing a potential translational avenue to enhance sensitivity to PARP inhibition. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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      – SubjectFull: Castration-resistant prostate cancer
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      – SubjectFull: Homologous recombination
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