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APE1 and NPM1 protect cancer cells from platinum compounds cytotoxicity and their expression pattern has a prognostic
Matilde Clarissa Malfatti1, Lorenzo Gerratana1,2, Emiliano Dalla1
1Department of Medicine (DAME), University of Udine, Piazzale M. Kolbe 4, 33100, Udine, Italy.
Background:
Triple negative breast cancer (TNBC) is a breast cancer subgroup characterized by a lack of hormone receptors' expression and no HER2 overexpression. These molecular features both drastically reduce treatment options and confer poor prognosis. Platinum (Pt)-salts are being investigated as a new therapeutic strategy. The base excision repair (BER) pathway is important for resistance to Pt-based therapies. Overexpression of APE1, a pivotal enzyme of the BER pathway, as well as the expression of NPM1, a functional regulator of APE1, are associated with poor outcome and resistance to Pt-based therapies.
Methods:
We evaluated the role of NPM1, APE1 and altered NPM1/APE1 interaction in the response to Pt-salts treatment in different cell lines: APE1 knockout (KO) cells, NPM1 KO cells, cell line models having an altered APE1/NPM1 interaction and HCC70 and HCC1937 TNBC cell lines, having different levels of APE1/NPM1. We evaluated the TNBC cells response to new chemotherapeutic small molecules targeting the endonuclease activity of APE1 or the APE1/NPM1 interaction, in combination with Pt-salts treatments. Expression levels' correlation between APE1 and NPM1 and their impact on prognosis was analyzed in a cohort of TNBC patients through immunohistochemistry. Bioinformatics analysis, using TCGA datasets, was performed to predict a molecular signature of cancers based on APE1 and NPM1 expression.
Results:
APE1 and NPM1, and their interaction as well, protect from the cytotoxicity induced by Pt-salts treatment. HCC1937 cells, having higher levels of APE1/NPM1 proteins, are more resistant to Pt-salts treatment compared to the HCC70 cells. A sensitization effect by APE1 inhibitors to Pt-compounds was observed. The association of NPM1/APE1 with cancer gene signatures highlighted alterations concerning cell-cycle dependent proteins.
Conclusions:
APE1 and NPM1 protect cancer cells from Pt-compounds cytotoxicity, suggesting a possible improvement of the activity of Pt-based therapy for TNBC, using the NPM1 and APE1 proteins as secondary therapeutic targets. Based on positive or negative correlation with APE1 and NPM1 gene expression levels, we finally propose several TNBC gene signatures that should deserve further attention for their potential impact on TNBC precision medicine approaches.
Insights
Triple negative breast cancer (TNBC) cells are protected from platinum-salts treatment by APE1 and NPM1 proteins. Targeting these proteins may improve platinum-based therapy efficacy in TNBC patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Triple-negative breast cancer (TNBC) lacks targeted therapy options and has a poor prognosis.
- Platinum (Pt)-salts are investigated for TNBC, but resistance is a challenge.
- The base excision repair (BER) pathway enzyme APE1 and its regulator NPM1 are linked to Pt-resistance.
Purpose of the Study:
- To investigate the role of NPM1, APE1, and their interaction in TNBC response to Pt-salts.
- To evaluate novel small molecules targeting APE1 or its interaction with NPM1 in combination with Pt-salts.
- To correlate APE1 and NPM1 expression with TNBC patient prognosis and identify predictive gene signatures.
Main Methods:
- Utilized APE1/NPM1 knockout and interaction-modified cell lines, along with TNBC cell lines (HCC70, HCC1937).
- Tested small molecules targeting APE1 endonuclease activity or APE1/NPM1 interaction alongside Pt-salts.
- Analyzed APE1/NPM1 expression correlation with prognosis in TNBC patients via immunohistochemistry and TCGA data.
Main Results:
- APE1 and NPM1, and their interaction, confer resistance to Pt-salts cytotoxicity.
- HCC1937 cells with higher APE1/NPM1 levels showed greater Pt-resistance than HCC70 cells.
- APE1 inhibitors sensitized TNBC cells to Pt-compounds, and NPM1/APE1 expression correlated with cell-cycle gene alterations.
Conclusions:
- APE1 and NPM1 protect TNBC cells from Pt-compound cytotoxicity.
- Targeting NPM1 and APE1 offers a strategy to enhance Pt-based therapy for TNBC.
- Identified potential TNBC gene signatures associated with APE1/NPM1 expression for precision medicine.
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