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Inosine monophosphate dehydrogenase 2 (IMPDH2) modulates response to therapy and chemo-resistance in triple negative
Tatiane da Silva Fernandes1, Bryan M Gillard2, Tao Dai1
1Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, CGP L3-317, Buffalo, NY, 14263, USA.
Abstract:
Triple negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer, whose high frequency of relapse is often due to resistance to chemotherapy. Here, we identify inosine monophosphate dehydrogenase 2 (IMPDH2) as a contributor to doxorubicin resistance, in multiple TNBC models. Analysis of publicly available datasets reveals elevated IMPDH2 expression to associate with worse overall TNBC prognosis in the clinic, including lower recurrence-free survival post adjuvant/neoadjuvant therapy. Importantly, both genetic depletion and pharmacological inhibition of IMPDH2 leads to reduction of pro-tumorigenic phenotypes in multiple doxorubicin-resistant TNBC models, both in vitro and in vivo. Overall, we propose IMPDH2 as a novel vulnerability that could be leveraged therapeutically to suppress and/or prevent the growth of chemo-resistant lesions.
Insights
Inosine monophosphate dehydrogenase 2 (IMPDH2) drives chemotherapy resistance in triple negative breast cancer (TNBC). Targeting IMPDH2 may overcome doxorubicin resistance and improve patient survival in TNBC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Triple negative breast cancer (TNBC) is an aggressive subtype with high relapse rates, often linked to chemotherapy resistance.
- Doxorubicin resistance significantly contributes to poor outcomes in TNBC patients.
Purpose of the Study:
- To identify novel molecular targets that contribute to doxorubicin resistance in TNBC.
- To investigate the therapeutic potential of targeting inosine monophosphate dehydrogenase 2 (IMPDH2) in chemo-resistant TNBC.
Main Methods:
- Utilized multiple in vitro and in vivo TNBC models exhibiting doxorubicin resistance.
- Performed genetic depletion and pharmacological inhibition of IMPDH2.
- Analyzed publicly available clinical datasets for IMPDH2 expression and patient prognosis.
Main Results:
- Identified IMPDH2 as a key contributor to doxorubicin resistance in TNBC.
- Found elevated IMPDH2 expression correlates with worse prognosis and lower recurrence-free survival in TNBC patients.
- Demonstrated that IMPDH2 inhibition reduces pro-tumorigenic phenotypes in resistant TNBC models.
Conclusions:
- IMPDH2 represents a novel therapeutic vulnerability in chemo-resistant triple negative breast cancer.
- Targeting IMPDH2 could be a strategy to overcome doxorubicin resistance and prevent disease progression.
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