Back to Search
Start Over
CHK2 activation contributes to the development of oxaliplatin resistance in colorectal cancer.
- Source :
-
British journal of cancer [Br J Cancer] 2022 Nov; Vol. 127 (9), pp. 1615-1628. Date of Electronic Publication: 2022 Aug 23. - Publication Year :
- 2022
-
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.<br />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.<br />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.<br />Conclusion: Our findings suggest that CHK2 activity is critical for modulating oxaliplatin response and that CHK2 is a potential therapeutic target for OR CRC.<br /> (© 2022. The Author(s).)
- Subjects :
- Humans
Cell Line, Tumor
Drug Resistance, Neoplasm genetics
Oxaliplatin pharmacology
Oxaliplatin therapeutic use
Phosphatidylinositol 3-Kinases
Protein Kinases
Colorectal Neoplasms drug therapy
Colorectal Neoplasms genetics
Colorectal Neoplasms pathology
Proteomics
Checkpoint Kinase 2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1532-1827
- Volume :
- 127
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- British journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 35999268
- Full Text :
- https://doi.org/10.1038/s41416-022-01946-9