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Novel markers of MCL1 inhibitor sensitivity in triple-negative breast cancer cells
Lei Duan1, Mehrdad Jafari Tadi1, Kelsey M O'Hara1
1Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, Illinois, USA.
Abstract:
Triple-negative breast cancer (TNBC) is an aggressive breast cancer sub-type with limited treatment options and poor prognosis. Currently, standard treatments for TNBC include surgery, chemotherapy, and anti-PDL1 therapy. These therapies have limited efficacy in advanced stages. Myeloid-cell leukemia 1 (MCL1) is an anti-apoptotic BCL2 family protein. High expression of MCL1 contributes to chemotherapy resistance and is associated with a worse prognosis in TNBC. MCL1 inhibitors are in clinical trials for TNBC, but response rates to these inhibitors can vary and predictive markers are lacking. Currently, we identified a 4-member (AXL, ETS1, IL6, EFEMP1) gene signature (GS) that predicts MCL1 inhibitor sensitivity in TNBC cells. Factors encoded by these genes regulate signaling pathways to promote MCL1 inhibitor resistance. Small molecule inhibitors of the GS factors can overcome resistance and sensitize otherwise resistant TNBC cells to MCL1 inhibitor treatment. These findings offer insights into potential therapeutic strategies and tumor stratification for MCL1 inhibitor use in TNBC.
Insights
A new gene signature predicts sensitivity to MCL1 inhibitors in triple-negative breast cancer (TNBC). Targeting these genes can overcome resistance, improving treatment for this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Triple-negative breast cancer (TNBC) is aggressive with limited treatment options.
- Myeloid-cell leukemia 1 (MCL1) overexpression drives chemotherapy resistance and poor prognosis in TNBC.
- MCL1 inhibitors show promise but lack predictive markers for patient response.
Purpose of the Study:
- To identify biomarkers predicting sensitivity to MCL1 inhibitors in TNBC.
- To investigate therapeutic strategies to overcome MCL1 inhibitor resistance.
Main Methods:
- Identification of a 4-gene signature (AXL, ETS1, IL6, EFEMP1) predictive of MCL1 inhibitor sensitivity.
- Analysis of gene functions in regulating resistance pathways.
- Testing small molecule inhibitors targeting the gene signature.
Main Results:
- The 4-gene signature accurately predicts MCL1 inhibitor sensitivity in TNBC cells.
- Genes in the signature regulate pathways contributing to MCL1 inhibitor resistance.
- Targeting signature genes with small molecules resensitizes resistant TNBC cells to MCL1 inhibitors.
Conclusions:
- The identified gene signature can stratify TNBC patients for MCL1 inhibitor therapy.
- Targeting the AXL, ETS1, IL6, and EFEMP1 genes offers a novel strategy to enhance MCL1 inhibitor efficacy.
- These findings pave the way for improved therapeutic strategies and patient selection in TNBC treatment.
