Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps

Dias, Mariana Paes; Tripathi, Vivek; Heijden, Ingrid van der; Cong, Ke; Manolika, Eleni Maria; Bhin, Jinhyuk; Gogola, Ewa; Galanos, Panagiotis; Annunziato, Stefano; Lieftink, Cor; Andújar-Sánchez, Miguel; Chakrabarty, Sanjiban; Smith, Graeme C.M.; Ven, Marieke van de; Beijersbergen, Roderick L.; Bártková, Jiřina; Rottenberg, Sven; Cantor, Sharon B.; Bártek, Jiří; Chaudhuri, Arnab Ray; Jonkers, Jos

doi:10.1016/j.molcel.2021.09.005

Cited by 45 publications

(29 citation statements)

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“… Note: While a cycle of 28 days is standard for olaparib treatment, 56 days can also be used in order to observe a better window between the different lines. For hypersensitization experiments (increase response in already responsive lines/combination experiments), 50 mg/kg olaparib may be ideal ( Paes Dias et al., 2021b ). Sacrifice animals with CO 2 when the tumor volume reaches 1500 mm 3 .…”

Section: Step-by-step Methods Detailsmentioning

confidence: 99%

“…Tumoroids can be easily genetically modified and, compared to 2D, screens in 3D tumoroids have the advantage of using cells that retain crucial features of the original tumor (e.g., morphology, drug response, 3D structure) and that require a small culturing surface area (1 million tumoroid cells can fit in a few wells while 1 million 2D cells require one or more 15 cm dishes). The protocol below describes the specific steps to carry out functional genetic dropout screens using PARPi-resistant mouse mammary tumoroids to identify new therapeutic targets to improve response to PARPi and revert resistance, as in Paes Dias et al. (2021b) .…”

Section: Before You Beginmentioning

confidence: 99%

“…This protocol details the steps for carrying out functional genetic dropout screens using mouse mammary tumoroids. While this protocol can be applied to other research aims, we focused on the use of PARPi-resistant tumoroids for the identification of genes whose loss reverts resistance to PARPi, as in Paes Dias et al. (2021b) .…”

Section: Expected Outcomesmentioning

confidence: 99%

“…The purpose of this protocol is to screen for therapeutic targets and allow rapid and straightforward in vivo validation of the candidate targets. For complete details on the use and execution of this protocol, please refer to Paes Dias et al. (2021b) .…”

mentioning

confidence: 99%

“…For complete details on the use and execution of this protocol, please refer to Paes Dias et al. (2021b) .…”

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confidence: 99%

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Functional genetic dropout screens and in vivo validation of candidate therapeutic targets using mouse mammary tumoroids

2022

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Summary We have previously developed 3D tumoroids derived from genetically engineered mouse models (GEMMs) of BRCA1/2-deficient breast cancer. Here, we describe how to genetically modify tumoroids, use them for functional genetic dropout screens, and carry out orthotopic transplantation of modified tumoroids. The purpose of this protocol is to screen for therapeutic targets and allow rapid and straightforward in vivo validation of the candidate targets. For complete details on the use and execution of this protocol, please refer to Paes Dias et al. (2021b) .

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Section: Step-by-step Methods Detailsmentioning

confidence: 99%

Section: Before You Beginmentioning

confidence: 99%

Section: Expected Outcomesmentioning

confidence: 99%

mentioning

confidence: 99%

“…For complete details on the use and execution of this protocol, please refer to Paes Dias et al. (2021b) .…”

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confidence: 99%

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Functional genetic dropout screens and in vivo validation of candidate therapeutic targets using mouse mammary tumoroids

2022

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DNA repair as a shared hallmark in cancer and ageing

Clarke

Mostoslavsky

2022

Molecular Oncology

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Increasing evidence demonstrates that DNA damage and genome instability play a crucial role in ageing. Mammalian cells have developed a wide range of complex and well‐orchestrated DNA repair pathways to respond to and resolve many different types of DNA lesions that occur from exogenous and endogenous sources. Defects in these repair pathways lead to accelerated or premature ageing syndromes and increase the likelihood of cancer development. Understanding the fundamental mechanisms of DNA repair will help develop novel strategies to treat ageing‐related diseases. Here, we revisit the processes involved in DNA damage repair and how these can contribute to diseases, including ageing and cancer. We also review recent mechanistic insights into DNA repair and discuss how these insights are being used to develop novel therapeutic strategies for treating human disease. We discuss the use of PARP inhibitors in the clinic for the treatment of breast and ovarian cancer and the challenges associated with acquired drug resistance. Finally, we discuss how DNA repair pathway‐targeted therapeutics are moving beyond PARP inhibition in the search for ever more innovative and efficacious cancer therapies.

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