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 T.; Morris, Robert T.; Lauffer, Sam; Nussenzweig, André; Ramaswamy, Sridhar; Benes, Cyril H.; Haber, Daniel A.; Maheswaran, Shyamala; Birrer, Michael J.; Zou, Lee

doi:10.1101/gad.290957.116

Cited by 316 publications

(330 citation statements)

References 82 publications

(101 reference statements)

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“…Whereas HCC1397 cells demonstrated robust RAD51 IRIF in the absence of a detectable BRCA1 protein. Such cell line variations may stem from the activity of additional factors that contribute to PALB2 recruitment to DNA breaks such as RNF168, ATR or RPA (Luijsterburg et al, 2017; Murphy et al, 2014; Yazinski et al, 2017). Moreover, KO of DNA end resection inhibitory proteins involved in the shieldin complex were recently shown to promote PARPi resistance in a range of human and mouse BRCA1 mutant cell lines (Barazas et al, 2018; Dev et al, 2018; Mirman et al, 2018; Noorder-meer et al, 2018; Tomida et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance

et al. 2018

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SUMMARY BRCA1 functions in homologous recombination (HR) both up- and downstream of DNA end resection. However, in cells with 53BP1 gene knockout (KO), BRCA1 is dispensable for the initiation of resection, but whether BRCA1 activity is entirely redundant after end resection is unclear. Here, we found that 53bp1 KO rescued the embryonic viability of a Brea1ΔC/ΔC mouse model that harbors a stop codon in the coiled-coil domain. However, Brca1ΔC/ΔC;53bp1−/− mice were susceptible to tumor formation, lacked Rad51 foci, and were sensitive to PARP inhibitor (PARPi) treatment, indicative of suboptimal HR. Furthermore, BRCA1 mutant cancer cell lines were dependent on truncated BRCA1 proteins that retained the ability to interact with PALB2 for 53BP1 KO induced RAD51 foci and PARPi resistance. Our data suggest that the overall efficiency of 53BP1 loss of function induced HR may be BRCA1 mutation dependent. In the setting of 53BP1 KO, hypomorphic BRCA1 proteins are active downstream of end resection, promoting RAD51 loading and PARPi resistance.

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Section: Discussionmentioning

confidence: 99%

BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance

et al. 2018

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“…Defects in replication fork protection are correlated with sensitivity to ATR inhibitors (ATRi), and patients who do not exhibit defects in HR but have unstable replication forks may benefit from ATRi therapies (Hill et al ., ). Furthermore, ATRi is also a viable option to target BRCA‐deficient cancer cells that have acquired resistance to PARPi, by inhibiting the ‘rewired’ HR pathway that is promotes resistance to PARP inhibition (Haynes et al ., ; Yazinski et al ., ). For these reasons, ATR is an attractive target to disrupt DNA repair in cancer cells.…”

Section: Alternative Dna Repair‐targeting Therapies For Use In Colorementioning

confidence: 98%

Exploiting DNA repair defects in colorectal cancer

et al. 2019

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Colorectal cancer ( CRC ) is the third leading cause of cancer‐related deaths worldwide. Therapies that take advantage of defects in DNA repair pathways have been explored in the context of breast, ovarian, and other tumor types, but not yet systematically in CRC . At present, only immune checkpoint blockade therapies have been FDA approved for use in mismatch repair‐deficient colorectal tumors. Here, we discuss how systematic identification of alterations in DNA repair genes could provide new therapeutic opportunities for CRC s. Analysis of The Cancer Genome Atlas Colon Adenocarcinoma ( TCGA ‐ COAD ) and Rectal Adenocarcinoma ( TCGA ‐ READ ) PanCancer Atlas datasets identified 141 (out of 528) cases with putative driver mutations in 29 genes associated with DNA damage response and repair, including the mismatch repair and homologous recombination pathways. Genetic defects in these pathways might confer repair‐deficient characteristics, such as genomic instability in the absence of homologous recombination, which can be exploited. For example, inhibitors of poly( ADP )‐ribose polymerase are effectively used to treat cancers that carry mutations in BRCA 1 and/or BRCA 2 and have shown promising results in CRC preclinical studies. HR deficiency can also occur in cells with no detectable BRCA 1/ BRCA 2 mutations but exhibiting BRCA ‐ like phenotypes. DNA repair‐targeting therapies, such as ATR and CHK 1 inhibitors (which are most effective against cancers carrying ATM mutations), can be used in combination with current genotoxic chemotherapies in CRC s to further improve therapy response. Finally, therapies that target alternative DNA repair mechanisms, such as thiopurines, also have the potential to confer increased sensitivity to current chemotherapy regimens, thus expanding the spectrum of therapy options and potentially improving clinical outcomes for CRC patients.

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“…ATR is a key regulator of homologous recombination-mediated repair ATR's primary action occurs in S phase, a period during the cell cycle where a sister DNA template is available for homologydirected repair, and it functions mainly as a pro-HR kinase. Depletion or inhibition of ATR impairs the ability of cells to utilize HR and leads to synergistic cell death with replication stress-inducing drugs (Wang et al, 2004a;Vriend et al, 2016;Yazinski et al, 2017;Kim et al, 2018). One model proposes that during HR-mediated repair, an ATM-to-ATR transition occurs, where ATM initiates resection and triggers the ATR activation that governs the later steps of homologous recombination (Cuadrado et al, 2006;Shiotani & Zou, 2009).…”

Section: Phosphorylation Control Of the Homologous Recombination Machmentioning

confidence: 99%

DNA damage kinase signaling: checkpoint and repair at 30 years

2019

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From bacteria to mammalian cells, damaged DNA is sensed and targeted by DNA repair pathways. In eukaryotes, kinases play a central role in coordinating the DNA damage response. DNA damage signaling kinases were identified over two decades ago and linked to the cell cycle checkpoint concept proposed by Weinert and Hartwell in 1988. Connections between the DNA damage signaling kinases and DNA repair were scant at first, and the initial perception was that the importance of these kinases for genome integrity was largely an indirect effect of their roles in checkpoints, DNA replication, and transcription. As more substrates of DNA damage signaling kinases were identified, it became clear that they directly regulate a wide range of DNA repair factors. Here, we review our current understanding of DNA damage signaling kinases, delineating the key substrates in budding yeast and humans. We trace the progress of the field in the last 30 years and discuss our current understanding of the major substrate regulatory mechanisms involved in checkpoint responses and DNA repair.

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

Cited by 316 publications

References 82 publications

BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance

BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance

Exploiting DNA repair defects in colorectal cancer

DNA damage kinase signaling: checkpoint and repair at 30 years

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