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- Title
CHK2 activation contributes to the development of oxaliplatin resistance in colorectal cancer.
- Authors
Hsieh, Chi-Che; Hsu, Sen-Huei; Lin, Chih-Yu; Liaw, Hung-Jiun; Li, Ting-Wei; Jiang, Kuan-Ying; Chiang, Nai-Jung; Chen, Shang-Hung; Lin, Bo-Wen; Chen, Po-Chuan; Chan, Ren-Hao; Lin, Peng-Chan; Yeh, Yu-Min; Shen, Che-Hung
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>Our findings suggest that CHK2 activity is critical for modulating oxaliplatin response and that CHK2 is a potential therapeutic target for OR CRC.
- Publication
British Journal of Cancer, 2022, Vol 127, Issue 9, p1615
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/s41416-022-01946-9