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

Cited 12 time in Web of Science Cited 10 time in Scopus
Authors

Oh, Kyoung-Seok; Nam, Ah-Rong; Bang, Ju-Hee; Seo, Hye-Rim; Kim, Jae-Min; Yoon, Jeesun; Kim, Tae-Yong; Oh, Do-Youn

Issue Date
2022-08
Publisher
Nature Publishing Group
Citation
Oncogene, Vol.41 No.32, pp.3939-3952
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.
ISSN
0950-9232
URI
https://hdl.handle.net/10371/212743
DOI
https://doi.org/10.1038/s41388-022-02384-w
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  • College of Medicine
  • Department of Medicine
Research Area DNA 손상 반응 타겟 물질의 면역조절 효과, Effect of DNA damage response target substances on immunomodulatory action, Efficacy and biomarker validation studies of targeted therapeutics, Resistance mechanisms according to targeted therapeutics, 표적 항암제 내성 기전 연구, 표적 항암제의 효과 검증 및 바이오마커 규명

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