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Combined inhibition of Wee1 and Chk1 as a therapeutic strategy in multiple myeloma
Angélique Bruyer1, Laure Dutrieux2, Hugues de Boussac1
1Diag2Tec, Montpellier, France.
Abstract:
Multiple myeloma (MM) is a hematological malignancy characterized by an abnormal clonal proliferation of malignant plasma cells. Despite the introduction of novel agents that have significantly improved clinical outcome, most patients relapse and develop drug resistance. MM is characterized by genomic instability and a high level of replicative stress. In response to replicative and DNA damage stress, MM cells activate various DNA damage signaling pathways. In this study, we reported that high CHK1 and WEE1 expression is associated with poor outcome in independent cohorts of MM patients treated with high dose melphalan chemotherapy or anti-CD38 immunotherapy. Combined targeting of Chk1 and Wee1 demonstrates synergistic toxicities on MM cells and was associated with higher DNA double-strand break induction, as evidenced by an increased percentage of γH2AX positive cells subsequently leading to apoptosis. The therapeutic interest of Chk1/Wee1 inhibitors' combination was validated on primary MM cells of patients. The toxicity was specific of MM cells since normal bone marrow cells were not significantly affected. Using deconvolution approach, MM patients with high CHK1 expression exhibited a significant lower percentage of NK cells whereas patients with high WEE1 expression displayed a significant higher percentage of regulatory T cells in the bone marrow. These data emphasize that MM cell adaptation to replicative stress through Wee1 and Chk1 upregulation may decrease the activation of the cell-intrinsic innate immune response. Our study suggests that association of Chk1 and Wee1 inhibitors may represent a promising therapeutic approach in high-risk MM patients characterized by high CHK1 and WEE1 expression.
Insights
Targeting Chk1 and Wee1 shows promise for multiple myeloma (MM) patients with high expression of these proteins. Combining inhibitors synergistically kills MM cells, offering a potential new therapy for high-risk cases.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Multiple myeloma (MM) is a plasma cell malignancy with poor outcomes due to relapse and drug resistance.
- MM cells exhibit genomic instability and replicative stress, activating DNA damage response pathways.
- High expression of CHK1 and WEE1 is linked to adverse outcomes in MM patients.
Purpose of the Study:
- To investigate the role of CHK1 and WEE1 in MM progression and treatment resistance.
- To evaluate the efficacy of combined Chk1 and Wee1 inhibition in MM.
- To explore the impact of CHK1 and WEE1 expression on the bone marrow immune microenvironment in MM.
Main Methods:
- Analysis of CHK1 and WEE1 expression in independent MM patient cohorts.
- In vitro studies combining Chk1 and Wee1 inhibitors on MM cell lines and primary patient cells.
- Assessment of DNA double-strand breaks (γH2AX) and apoptosis induction.
- Deconvolution analysis to examine immune cell populations in the bone marrow.
Main Results:
- High CHK1 and WEE1 expression correlated with poor outcomes in MM patients treated with melphalan or anti-CD38 immunotherapy.
- Combined Chk1/Wee1 inhibition demonstrated synergistic toxicity against MM cells, inducing DNA damage and apoptosis.
- Normal bone marrow cells showed minimal toxicity to the combined inhibitors.
- High CHK1 expression was associated with lower NK cell percentages, while high WEE1 expression correlated with higher regulatory T cell percentages in MM patients.
Conclusions:
- CHK1 and WEE1 upregulation in MM cells may contribute to immune evasion by suppressing innate immune responses.
- Combined Chk1 and Wee1 inhibition represents a potential therapeutic strategy for high-risk MM patients with elevated CHK1/WEE1 expression.
- Targeting these pathways could overcome treatment resistance and improve clinical outcomes in multiple myeloma.
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