Radiosensitivity Is an Acquired Vulnerability of PARPi-Resistant BRCA1-Deficient Tumors

Barazas, Marco; Gasparini, Alessia; Huang, Yike; Küçükosmanoğlu, Aslı; Annunziato, Stefano; Bouwman, Peter; Sol, Wendy; Kersbergen, Ariena; Proost, Natalie; Korte-Grimmerink, Renske de; Ven, Marieke van de; Jonkers, Jos; Borst, Gerben R.; Rottenberg, Sven

doi:10.1158/0008-5472.can-18-2077

Cited by 44 publications

(39 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, in the majority of genetic models currently reported, restored FP fails to restore cisplatin resistance, suggesting the cisplatin lesions do not collapse forks, and therefore calls into question how cisplatin crosslinks could be converted into DSBs (4,10). Most saliently, indicating that the fundamental sensitizing lesion may in fact not be a DSB, reports indicate even HR proficient cells can nevertheless display hypersensitivity to cisplatin and other genotoxic agents (11)(12)(13). Moreover, in addition to cisplatin, BRCA-deficient cells and patient tumors have recently been found to be hypersensitive to a wide range of genotoxic agents that were previously thought to be mechanistically distinct, including doxorubicin, Poly(ADP-ribose) polymerase 1 inhibition (PARPi), and other first-line agents, even including the platinum analog oxaliplatin, which is not thought to generate DSBs (14).…”

mentioning

confidence: 99%

Replication Gaps Underlie BRCA Deficiency and Therapy Response

et al. 2021

View full text Add to dashboard Cite

Defects in DNA repair and the protection of stalled DNA replication forks are thought to underlie the chemosensitivity of tumors deficient in the hereditary breast cancer genes BRCA1 and BRCA2 (BRCA). Challenging this assumption are recent findings that indicate chemotherapies, such as cisplatin used to treat BRCA-deficient tumors, do not initially cause DNA double-strand breaks (DSB). Here, we show that ssDNA replication gaps underlie the hypersensitivity of BRCA-deficient cancer and that defects in homologous recombination (HR) or fork protection (FP) do not. In BRCA-deficient cells, ssDNA gaps developed because replication was not effectively restrained in response to stress. Gap suppression by either restoration of fork restraint or gap filling conferred therapy resistance in tissue culture and BRCA patient tumors. In contrast, restored FP and HR could be uncoupled from therapy resistance when gaps were present. Moreover, DSBs were not detected after therapy when apoptosis was inhibited, supporting a framework in which DSBs are not directly induced by genotoxic agents, but rather are induced from cell death nucleases and are not fundamental to the mechanism of action of genotoxic agents. Together, these data indicate that ssDNA replication gaps underlie the BRCA cancer phenotype, “BRCAness,” and we propose they are fundamental to the mechanism of action of genotoxic chemotherapies. Significance: This study suggests that ssDNA replication gaps are fundamental to the toxicity of genotoxic agents and underlie the BRCA-cancer phenotype “BRCAness,” yielding promising biomarkers, targets, and opportunities to resensitize refractory disease. See related commentary by Canman, p. 1214

show abstract

mentioning

confidence: 99%

Replication Gaps Underlie BRCA Deficiency and Therapy Response

et al. 2021

View full text Add to dashboard Cite

show abstract

“…DNA-PK inhibitors, as DNA-damage inducers, are undergoing clinical trials and have good prospects for prognosis in combination with radiotherapy. Studies have validated the finding that loss of 53BP1/RIF1/ REV7/Shieldin/CST pathway in BRCA1-proficient cells restored HR activity, which increased acquired vulnerable radiotherapy sensitivity both in vivo and in vitro (118). In addition, PARPi has been validated to increase the sensitivity to radiotherapy in BRCAness phenotype.…”

Section: Parpi Plus Radiotherapymentioning

confidence: 69%

New Perspectives for Resistance to PARP Inhibitors in Triple-Negative Breast Cancer

Han

et al. 2020

Front. Oncol.

View full text Add to dashboard Cite

Poly (ADP-ribose) polymerase (PARP) inhibitors are a therapeutic milestone exerting a synthetic lethal effect in the treatment of cancer involving BRCA1/2 mutation. Theoretically, PARP inhibitors (PARPi) eliminate tumor cells by disrupting DNA damage repair through either PARylation or the homologous recombination (HR) pathway. However, resistance to PARPi greatly hinders therapeutic effectiveness in triple-negative breast cancer (TNBC). Owing to the high heterogeneity and few genetic targets in TNBC, there has been limited therapeutic progress in the past decades. In view of this, there is a need to circumvent resistance to PARPi and develop potential treatment strategies for TNBC. We present, herein, a review of the scientific progress and explore the mechanisms underlying PARPi resistance in TNBC. The complicated mechanisms of PARPi resistance, including drug exporter formation, loss of poly (ADP-ribose) glycohydrolase (PARG), HR reactivation, and restoration of replication fork stability, are discussed in detail in this review. Additionally, we also discuss new combination therapies with PARPi that can improve the clinical response in TNBC. The new perspectives for PARPi bring novel challenges and opportunities to overcome PARPi resistance in breast cancer.

show abstract

“…A lack of response to treatment with a PARPi is often associated with an acquired resistance after long term exposure [25,96]. Therefore, recent years have seen a surge of interest in the combination of PARPi with other therapies which may revert resistant phenotypes, expanding the indication of these drugs beyond HRR deficient tumors [96,97]. Currently, a number of ongoing clinical trials are assessing, amongst other schemes, the effects of the combination of olaparib and IR on a wide range of tumors, from breast and ovarian to glioblastoma and lung cancers [98][99][100][101][102].…”

Section: Discussionmentioning

confidence: 99%

Zebrafish Xenografts Unveil Sensitivity to Olaparib beyond BRCA Status

Varanda

Martins-Logrado

Ferreira

et al. 2020

Cancers

View full text Add to dashboard Cite

Poly (ADP-ribose) polymerase (PARP) inhibition in BRCA-mutated cells results in an incapacity to repair DNA damage, leading to cell death caused by synthetic lethality. Within the treatment options for advanced triple negative breast cancer, the PARP inhibitor olaparib is only given to patients with BRCA1/2 mutations. However, these patients may show resistance to this drug and BRCA1/2 wild-type tumors can show a striking sensitivity, making BRCA status a poor biomarker for treatment choice. Aiming to investigate if the zebrafish model can discriminate sensitivities to olaparib, we developed zebrafish xenografts with different BRCA status and measured tumor response to treatment, as well as its impact on angiogenesis and metastasis. When challenged with olaparib, xenografts revealed sensitivity phenotypes independent of BRCA. Moreover, its combination with ionizing radiation increased the cytotoxic effects, showing potential as a combinatorial regimen. In conclusion, we show that the zebrafish xenograft model may be used as a sensitivity profiling platform for olaparib in monotherapy or in combinatorial regimens. Hence, this model presents as a promising option for the future establishment of patient-derived xenografts for personalized medicine approaches beyond BRCA status.

show abstract

Radiosensitivity Is an Acquired Vulnerability of PARPi-Resistant BRCA1-Deficient Tumors

Cited by 44 publications

References 25 publications

Replication Gaps Underlie BRCA Deficiency and Therapy Response

Replication Gaps Underlie BRCA Deficiency and Therapy Response

New Perspectives for Resistance to PARP Inhibitors in Triple-Negative Breast Cancer

Zebrafish Xenografts Unveil Sensitivity to Olaparib beyond BRCA Status

Contact Info

Product

Resources

About