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Published on: September 30, 2016
CHK2 activation contributes to the development of oxaliplatin resistance in colorectal cancer
Chi-Che Hsieh1, Sen-Huei Hsu2, Chih-Yu Lin1
1National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan.
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.
Insights
Checkpoint kinase 2 (CHK2) activity is crucial for oxaliplatin resistance in colorectal cancer (CRC). Inhibiting CHK2 shows promise for overcoming drug resistance and improving patient survival in CRC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Colorectal cancer (CRC) is a leading cause of cancer morbidity and mortality.
- Oxaliplatin resistance significantly reduces survival in CRC patients.
- Identifying mechanisms of oxaliplatin resistance is vital for new therapeutic strategies.
Purpose of the Study:
- To identify key molecules involved in oxaliplatin resistance in CRC.
- To investigate the role of CHK2 in the development of oxaliplatin resistance.
Main Methods:
- Proteomic screening of oxaliplatin-resistant (OR) CRC tumor spheroids.
- Biochemical assays and in vitro/in vivo models to characterize CHK2 function.
- Utilized CHK2 mutants and a CHK2 inhibitor (BML-277).
Main Results:
- Elevated phospho-CHK2(Thr68) levels were observed in OR CRC cells and patient samples.
- Oxaliplatin activates PIKKs and CHK2, enhancing CHK2/PARP1 interaction for DNA repair.
- CHK2 inhibition reduced DNA repair pathways (PARylation, FANCD2 monoubiquitination, homologous recombination) and OR CRC cell growth.
Conclusions:
- CHK2 activity is critical for modulating the response to oxaliplatin in CRC.
- CHK2 represents a potential therapeutic target for overcoming oxaliplatin resistance in CRC.
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