CHK2 activation contributes to the development of oxaliplatin resistance in colorectal cancer

Chi Che Hsieh, Sen Huei Hsu, Chih Yu Lin, Hung Jiun Liaw, Ting Wei Li, Kuan Ying Jiang, Nai Jung Chiang, Shang Hung Chen, Bo Wen Lin, Po Chuan Chen, Ren Hao Chan, Peng Chan Lin, Yu Min Yeh, Che Hung Shen

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Colorectal cancer (CRC), the most common cancer type, causes high morbidity and mortality. Patients who develop drug resistance to oxaliplatin-based regimens have short overall survival. Thus, identifying molecules involved in the development of oxaliplatin resistance is critical for designing therapeutic strategies. Methods: A proteomic screen was performed to reveal altered protein kinase phosphorylation in oxaliplatin-resistant (OR) CRC tumour spheroids. The function of CHK2 was characterised using several biochemical techniques and evident using in vitro cell and in vivo tumour models. Results: We revealed that the level of phospho-CHK2(Thr68) was elevated in OR CRC cells and in ~30% of tumour samples from patients with OR CRC. We demonstrated that oxaliplatin activated several phosphatidylinositol 3-kinase-related kinases (PIKKs) and CHK2 downstream effectors and enhanced CHK2/PARP1 interaction to facilitate DNA repair. A phosphorylation mimicking CHK2 mutant, CHK2T68D, but not a kinase-dead CHK2 mutant, CHK2D347A, promoted DNA repair, the CHK2/PARP1 interaction, and cell growth in the presence of oxaliplatin. Finally, we showed that a CHK2 inhibitor, BML-277, reduced protein poly(ADP-ribosyl)ation (PARylation), FANCD2 monoubiquitination, homologous recombination and OR CRC cell growth in vitro and in vivo. Conclusion: Our findings suggest that CHK2 activity is critical for modulating oxaliplatin response and that CHK2 is a potential therapeutic target for OR CRC.

Original languageEnglish
Pages (from-to)1615-1628
Number of pages14
JournalBritish Journal of Cancer
Volume127
Issue number9
DOIs
Publication statusPublished - 2022 Nov 1

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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