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A synthetic lethal strategy using PARP and ATM inhibition for overcoming trastuzumab resistance in HER2-positive cancers

Abstract

Despite its clinical efficacy in HER2-positive cancers, resistance to trastuzumab inevitably occurs. The DNA damage response (DDR) pathway is essential for maintaining genomic stability and cell survival. However, the role of the DDR pathway in HER2-positive tumors and trastuzumab resistance remains elusive. In this study, we verified that increased PARP1 expression in trastuzumab-resistant (TR) cells, owing to its augmented stability by escape from proteasomal degradation, confers tolerability to trastuzumab-induced DNA damage. Interruption of PARP1 in TR cells restrains its cellular growth, while simultaneously activating ATM to retain its genome stability. Dual inhibition of PARP and ATM induces synthetic lethality in TR cells by favoring the toxic NHEJ pathway instead of the HRR pathway. Our results highlight the potential of clinical development of DDR-targeting strategies for trastuzumab-resistant HER2-positive cancer patients.

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Fig. 1: TR cells sustains the functional DDR pathway to restore DSBs induced by trastuzumab.
Fig. 2: PARP1 is upregulated in trastuzumab-resistant (TR) cells, and functions distinctive from parental cells.
Fig. 3: Trastuzumab-resistant (TR) cells are vulnerable to PARP inhibition.
Fig. 4: PARP inhibition enhances DNA damage in trastuzumab-resistant (TR) cells.
Fig. 5: Synthetic lethal interaction between PARP and ataxia-telangiectasia mutated protein (ATM) in trastuzumab-resistant (TR) cells.
Fig. 6: Non-homologous end joining (NHEJ) dependency drives hypersensitivity of trastuzumab-resistant (TR) cells to PARP and ATM inhibition.
Fig. 7: Dual inhibition of PARP and ATM shows potent antitumor activity in the xenograft model.

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Acknowledgements

This research was supported by the SNUH research fund (Grant No. 03-2019-0220) and the Institute of Smart Healthcare Innovative Medical Sciences, a Brain Korea 21 four program, Seoul National University, and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (Grant No. 2021R1A2C2007430). This research was also supported by 3rd AstraZeneca-KHIDI (Korea Health Industry Development Institute) oncology research program (Grant No. 06-2016-2920).

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Concept: Oh DY, Oh KS, Data generation: Oh KS, Analysis, interpretation: all. All authors approved the manuscript.

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Correspondence to Do-Youn Oh.

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Oh DY: Consultant or advisory board member of AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, and Yuhan. Research grant from AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, and Handok.

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Oh, KS., Nam, AR., Bang, JH. et al. A synthetic lethal strategy using PARP and ATM inhibition for overcoming trastuzumab resistance in HER2-positive cancers. Oncogene 41, 3939–3952 (2022). https://doi.org/10.1038/s41388-022-02384-w

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