Secondary Somatic Mutations Restoring <i>RAD51C</i> and <i>RAD51D</i> Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma

Kondrashova, Olga; Nguyen, Minh; Shield-Artin, Kristy; Tinker, Anna V.; Teng, Nelson N.H.; Harrell, Maria I.; Kuiper, Michael J.; Ho, Gwo-Yaw; Barker, Holly E.; Jasin, Maria; Prakash, Rohit; Kass, Elizabeth M.; Sullivan, Meghan R.; Brunette, Gregory J.; Bernstein, Kara A.; Coleman, Robert L.; Floquet, Anne; Friedlander, Michael; Kichenadasse, Ganessan; O’Malley, David M.; Oza, Amit M.; Sun, James; Robillard, Liliane; Maloney, Lara; Bowtell, David D.L.; Giordano, Heidi; Wakefield, Matthew J.; Kaufmann, Scott H.; Simmons, Andrew; Harding, Thomas C.; Raponi, Mitch; McNeish, Iain A.; Swisher, Elizabeth M.; Lin, Kevin K.; Scott, Clare L.

doi:10.1158/2159-8290.cd-17-0419

Cited by 340 publications

(283 citation statements)

References 48 publications

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“…As PARPi are increasingly being used for cancer therapy, understanding their resistance is becoming more and more significant and urgent. In fact, clinical resistance to PARPi, including olaparib, rucaparib and veliparib, has been reported. In addition, PARPi will probably extend their application to non‐BRCA/ATM‐mutated cancers .…”

Section: Discussionmentioning

confidence: 99%

Acquired resistance of phosphatase and tensin homolog‐deficient cells to poly(ADP‐ribose) polymerase inhibitor and Ara‐C mediated by 53BP1 loss and SAMHD1 overexpression

et al. 2018

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With increasing uses of poly(ADP‐ribose) polymerase (PARP) inhibitors (PARPi) for cancer therapy, understanding their resistance is becoming urgent. However, acquired PARPi resistance in the phosphatase and tensin homolog (PTEN)‐deficient background is poorly understood. We generated 3 PARPi‐resistant PTEN‐deficient glioblastoma U251 variants separately with olaparib (U251/OP), talazoparib (U251/TP) and simmiparib (U251/SP). These variants displayed consistent resistance (2.46‐71.78‐fold) to all 5 PARPi, including niraparib and rucaparib, and showed higher degrees of resistance to the PARPi to which the parental cells were more sensitive. The resistance was characteristic of fast emergence and high stability. However, the resistance acquirement did not cause an increasingly aggressive phenotype. The resistance was not correlated to various factors, including PTEN mutations. The PARPi‐treated variants produced less γH2AX and G2/M arrest. Consistently, loss of 53BP1 occurred in all variants and its compensation enhanced their sensitivity to PARPi by approximately 76%. The variants revealed slightly different cross‐resistance profiles to 13 non‐PARPi anticancer drugs. All were resistant to Ara‐C (6‐8‐fold) but showed differential resistance to 5‐fluorouracil, gemcitabine and paclitaxel. Almost no resistance was observed to the rest drugs, including cisplatin. SAMHD1 was overexpressed in all the variants and its knockout completely restored their sensitivity to Ara‐C but did not affect their PARPi sensitivity. The present study demonstrates a consistent resistance profile to PARPi and a unique cross‐resistance profile to non‐PARPi drugs in different PARPi‐resistant U251 cells and reveals 53BP1 loss and SAMHD1 overexpression as the primary mechanisms responsible for their resistance to PARPi and Ara‐C, respectively. These effects probably result from heritable gene change(s) caused by persistent PARPi exposure.

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Section: Discussionmentioning

confidence: 99%

Acquired resistance of phosphatase and tensin homolog‐deficient cells to poly(ADP‐ribose) polymerase inhibitor and Ara‐C mediated by 53BP1 loss and SAMHD1 overexpression

et al. 2018

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“…The genomic instability of all HGSOCs and the deficiency in DNA repair in almost 50% of HGSOCs are vulnerabilities that have allowed susceptibility to platinum chemotherapy and PARP inhibitors. Tumor and circulating cell‐free DNA (cfDNA) analyses now demonstrate evolutionary adaptation in response to platinum chemotherapy and PARP inhibitors and, in some patients, result in the emergence of bridging reversion mutations, whereas in other patients they lead to multiple parallel mutations, which overcome the prior therapeutic vulnerability and confer resistance …”

Section: Improving Outcomesmentioning

confidence: 99%

“…Tumor and circulating cell-free DNA (cfDNA) analyses now demonstrate evolutionary adaptation in response to platinum chemotherapy and PARP inhibitors and, in some patients, result in the emergence of bridging reversion mutations, whereas in other patients they lead to multiple parallel mutations, which overcome the prior therapeutic vulnerability and confer resistance. 117,152…”

Section: Sensitivity and Resistance To Therapymentioning

confidence: 99%

Epithelial ovarian cancer: Evolution of management in the era of precision medicine

Lheureux

Braunstein

Oza

2019

CA A Cancer J Clinicians

1,041

867

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Ovarian cancer is the second most common cause of gynecologic cancer death in women around the world. The outcomes are complicated, because the disease is often diagnosed late and composed of several subtypes with distinct biological and molecular properties (even within the same histological subtype), and there is inconsistency in availability of and access to treatment. Upfront treatment largely relies on debulking surgery to no residual disease and platinum‐based chemotherapy, with the addition of antiangiogenic agents in patients who have suboptimally debulked and stage IV disease. Major improvement in maintenance therapy has been seen by incorporating inhibitors against poly (ADP‐ribose) polymerase (PARP) molecules involved in the DNA damage‐repair process, which have been approved in a recurrent setting and recently in a first‐line setting among women with BRCA1/BRCA2 mutations. In recognizing the challenges facing the treatment of ovarian cancer, current investigations are enlaced with deep molecular and cellular profiling. To improve survival in this aggressive disease, access to appropriate evidence‐based care is requisite. In concert, realizing individualized precision medicine will require prioritizing clinical trials of innovative treatments and refining predictive biomarkers that will enable selection of patients who would benefit from chemotherapy, targeted agents, or immunotherapy. Together, a coordinated and structured approach will accelerate significant clinical and academic advancements in ovarian cancer and meaningfully change the paradigm of care.

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“…Secondary mutations were also identified that same year in platinum-resistant BRCA1 -mutated ovarian cancers (185delAG and 2594delC) (Swisher et al 2008). BRCA1 and BRCA2 secondary mutations continue to be reported in multiple cancer types (e.g., Afghahi et al 2017, Pishvaian et al 2017) and, more recently, in other HDR pathway genes, in particular, the RAD51 paralog genes RAD51C and RAD51D (Kondrashova et al 2017). …”

Section: Mechanisms Of Resistance To Poly(adp-ribose) Polymerase Imentioning

confidence: 99%

Homology-Directed Repair and the Role of BRCA1, BRCA2, and Related Proteins in Genome Integrity and Cancer

Chen

Feng

Lim

et al. 2018

Annu. Rev. Cancer Biol.

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261

221

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Germ-line and somatic mutations in genes that promote homology-directed repair (HDR), especially BRCA1 and BRCA2, are frequently observed in several cancers, in particular, breast and ovary but also prostate and other cancers. HDR is critical for the error-free repair of DNA double-strand breaks and other lesions, and HDR factors also protect stalled replication forks. As a result, loss of BRCA1 or BRCA2 poses significant risks to genome integrity, leading not only to cancer predisposition but also to sensitivity to DNA-damaging agents, affecting therapeutic approaches. Here we review recent advances in our understanding of BRCA1 and BRCA2, including how they genetically interact with other repair factors, how they protect stalled replication forks, how they affect the response to aldehydes, and how loss of their functions links to mutation signatures. Importantly, given the recent advances with poly(ADP-ribose) polymerase inhibitors (PARPi) for the treatment of HDR-deficient tumors, we discuss mechanisms by which BRCA-deficient tumors acquire resistance to PARPi and other agents.

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Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma

Cited by 340 publications

References 48 publications

Acquired resistance of phosphatase and tensin homolog‐deficient cells to poly(ADP‐ribose) polymerase inhibitor and Ara‐C mediated by 53BP1 loss and SAMHD1 overexpression

Acquired resistance of phosphatase and tensin homolog‐deficient cells to poly(ADP‐ribose) polymerase inhibitor and Ara‐C mediated by 53BP1 loss and SAMHD1 overexpression

Epithelial ovarian cancer: Evolution of management in the era of precision medicine

Homology-Directed Repair and the Role of BRCA1, BRCA2, and Related Proteins in Genome Integrity and Cancer

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