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Published on: September 18, 2013
Efficacy of CHK inhibitors as single agents in MYC-driven lymphoma cells
P T Ferrao1, E P Bukczynska, R W Johnstone
1Molecular Oncology Laboratory and Cancer Therapeutics Program, Research Division, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia. petranel.ferrao@petermac.org
Abstract:
CHK1 and CHK2 function as effectors of cell cycle checkpoint arrest following DNA damage. Small molecule inhibitors of CHK proteins are under clinical evaluation in combination with chemotherapeutic agents known to induce DNA damage. We examined whether CHK inhibitors could be effective as single agents in malignant cells with inherent DNA damage because of deregulated expression of the oncogene c-Myc. Eμ-myc lymphoma cells showed a dramatic increase in the extent of DNA damage and DNA damage response (DDR) signalling within 1 h of treatment with CHK1 inhibitors followed by caspase-dependent apoptosis and cell death. In p53 wild-type/ARF null Eμ-myc lymphoma cells, apoptotic cell death was preceded by accumulation of DNA damage and the amount of DNA damage correlated with the extent of cell death. This effect was not observed in normal B cells indicating that DNA damage accumulation following CHK inhibition was specific to Eμ-myc lymphoma cells that exhibit inherent DNA damage because of MYC-induced replication stress. Similar results were obtained with another structurally distinct CHK-inhibitor. Eμ-myc p53 null lymphoma cells were more sensitive to a dual CHK1/CHK2 inhibitor than to a CHK1-specific inhibitor. In all cases, the level of DNA damage following treatment was the most consistent indicator of drug sensitivity. Our results suggest that CHK inhibitors would be beneficial therapeutic agents in MYC-driven cancers. We propose that inhibitors of CHK can act in a synthetically lethal manner in cancers with replication stress as a result of these cancers being reliant on CHK proteins for an effective DDR and cell survival.
Insights
CHK inhibitors effectively induce cancer cell death by increasing DNA damage in MYC-driven lymphomas. These CHK inhibitors show promise as single-agent therapies for cancers with replication stress.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Checkpoint kinase 1 and 2 (CHK1 and CHK2) are key regulators of cell cycle arrest in response to DNA damage.
- CHK inhibitors are being investigated in combination with DNA-damaging chemotherapy.
- Malignant cells with deregulated c-Myc oncogene expression often have inherent DNA damage.
Purpose of the Study:
- To evaluate the efficacy of CHK inhibitors as single agents in MYC-driven cancers with inherent DNA damage.
- To determine if CHK inhibition can induce apoptosis and cell death in these malignant cells.
- To identify biomarkers of sensitivity to CHK inhibitors.
Main Methods:
- Treatment of Eμ-myc lymphoma cells and normal B cells with CHK1-specific and dual CHK1/CHK2 inhibitors.
- Assessment of DNA damage, DNA damage response (DDR) signaling, and apoptosis.
- Correlation of drug sensitivity with the level of induced DNA damage.
Main Results:
- CHK1 inhibitors significantly increased DNA damage and triggered caspase-dependent apoptosis in Eμ-myc lymphoma cells.
- The accumulation of DNA damage correlated with the extent of cell death, specifically in MYC-driven lymphoma cells.
- Normal B cells did not exhibit increased DNA damage, indicating specificity.
- Dual CHK1/CHK2 inhibitors were more effective in p53-null cells than CHK1-specific inhibitors.
- The level of DNA damage consistently predicted drug sensitivity.
Conclusions:
- CHK inhibitors are effective single agents against MYC-driven cancers characterized by replication stress.
- These inhibitors induce synthetic lethality by overwhelming the DNA damage response in cancer cells reliant on CHK proteins.
- The extent of induced DNA damage serves as a reliable indicator for therapeutic response.
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