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Exploiting synthetic lethality to target BRCA1/2-deficient tumors: where we stand

Abstract

The principle of synthetic lethality, which refers to the loss of viability resulting from the disruption of two genes, which, individually, do not cause lethality, has become an attractive target approach due to the development and clinical success of Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi). In this review, we present the most recent findings on the use of PARPi in the clinic, which are currently approved for second-line therapy for advanced ovarian and breast cancer associated with mutations of BRCA1 or BRCA2 (BRCA1/2) genes. PARPi efficacy, however, appears to be limited by acquired and inherent resistance, highlighting the need for alternative and synergistic targets to eliminate these tumors. Here, we explore other identified synthetic lethal interactors of BRCA1/2, including DNA polymerase theta (POLQ), Fanconi anemia complementation group D2 (FANDC2), radiation sensitive 52 (RAD52), Flap structure-specific endonuclease 1 (FEN1), and apurinic/apyrimidinic endodeoxyribonuclease 2 (APE2), as well as other protein and nonprotein targets, for BRCA1/2-mutated cancers and their implications for future therapies. A wealth of information now exists for phenotypic and functional characterization of these novel synthetic lethal interactors of BRCA1/2, and leveraging these findings can pave the way for the development of new targeted therapies for patients suffering from these cancers.

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Fig. 1: PARP deficiency and synthetic lethality.
Fig. 2: RAD52 deficiency and synthetic lethality.
Fig. 3: POL θ deficiency and synthetic lethality.
Fig. 4: FANCD2 deficiency and synthetic lethality.
Fig. 5: FEN1 deficiency and synthetic lethality.
Fig. 6: APE2 (APEX2) deficiency and synthetic lethality.

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Acknowledgements

We thank M.A. Pujana for critical reading of the paper. We would also like to thank all the members of the Hakem laboratory for helpful discussions. We apologize to investigators we were unable to reference due to length limitations. RH holds the Lee K. and Margaret Lau Chair in Breast Cancer Research, which is a joint project with the University of Toronto and The Princess Margaret hospital. RH is supported by the Canadian Institutes of Health Research (FDN 143214), and the Canadian Cancer Society (705367 and 706439). PSP is supported by STARS21, Terry Fox Foundation, Princess Margaret Cancer Foundation, Department of Medical Biophysics, University of Toronto, and the Ontario Graduate Scholarship, Government of Ontario. AA is supported by Canada Graduate Scholarships for Master’s program, Ontario Graduate Scholarship, and the Department of Laboratory Medicine and Pathobiology, University of Toronto.

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Correspondence to Razq Hakem.

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Patel, P.S., Algouneh, A. & Hakem, R. Exploiting synthetic lethality to target BRCA1/2-deficient tumors: where we stand. Oncogene 40, 3001–3014 (2021). https://doi.org/10.1038/s41388-021-01744-2

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