Abstract
Intrinsic and acquired resistance to cisplatin remains a primary hurdle to treatment of high-grade serous ovarian cancer (HGSOC). Cisplatin selectively kills tumor cells by inducing DNA crosslinks that block replicative DNA polymerases. Single-stranded DNA (ssDNA) generated at resulting stalled replication forks (RF) is bound and protected by heterotrimeric replication protein A (RPA), which then serves as a platform for recruitment and activation of replication stress response factors. Cells deficient in this response are characterized by extensive ssDNA formation and excessive RPA recruitment that exhausts the available pool of RPA, which (i) inhibits RPA-dependent processes such as nucleotide excision repair (NER) and (ii) causes catastrophic failure of blocked RF. Here, we investigated the influence of RPA availability on chemosensitivity using a panel of human HGSOC cell lines. Our data revealed a striking correlation among these cell lines between cisplatin sensitivity and the inability to efficiently repair DNA via NER, specifically during S phase. Such defects in NER were attributable to RPA exhaustion arising from aberrant activation of DNA replication origins during replication stress. Reduced RPA availability promoted Mre11-dependent degradation of nascent DNA at stalled RF in cell lines exhibiting elevated sensitivity to cisplatin. Strikingly, defective S-phase NER, RF instability, and cisplatin sensitivity could all be rescued by ectopic overexpression of RPA. Taken together, our findings indicate that RPA exhaustion represents a major determinant of cisplatin sensitivity in HGSOC cell lines.Significance: The influence of replication protein A exhaustion on cisplatin sensitivity harbors important implications toward improving therapy of various cancers that initially respond to platinum-based agents but later relapse due to intrinsic or acquired drug resistance. Cancer Res; 78(19); 5561-73. ©2018 AACR.
Highlights
High-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy, with a 5-year survival rate of approximately 50% [1]
We sought to elucidate the role of DNA replication stress– induced replication protein A (RPA) exhaustion in promoting CDDP sensitivity using a panel of patient-derived HGSOC cell lines
We initially turned our attention to nucleotide excision repair (NER), which, as discussed earlier, (i) is believed to represent an important determinant of CDDP resistance in ovarian cancer and (ii) is sensitive to replication stress–induced fluctuations in RPA availability during S phase
Summary
High-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy, with a 5-year survival rate of approximately 50% [1]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Buisson: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
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