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Updated: Dec 8, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
PTEN status determines chemosensitivity to proteasome inhibition in cholangiocarcinoma
Tian-Yi Jiang1,2, Yu-Fei Pan2,3, Zheng-Hua Wan2
1International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China.
Abstract:
Patient-derived xenografts (PDXs) and PDX-derived cells (PDCs) are useful in preclinical research. We performed a drug screening assay using PDCs and identified proteasome inhibitors as promising drugs for cholangiocarcinoma (CCA) treatment. Furthermore, we determined that phosphate and tensin homology deleted on chromosome ten (PTEN) deficiency promotes protein synthesis and proteasome subunit expression and proteolytic activity, creating a dependency on the proteasome for cancer cell growth and survival. Thus, targeting the proteasome machinery with the inhibitor bortezomib inhibited the proliferation and survival of CCA cells lacking functional PTEN. Therapeutic evaluation of PDXs, autochthonous mouse models, and patients confirmed this dependency on the proteasome. Mechanistically, we found that PTEN promoted the nuclear translocation of FOXO1, resulting in the increased expression of BACH1 and MAFF BACH1 and MAFF are transcriptional regulators that recognize the antioxidant response element, which is present in genes encoding proteasome subunits. PTEN induced the accumulation and nuclear translocation of these proteins, which directly repressed the transcription of genes encoding proteasome subunits. We revealed that the PTEN-proteasome axis is a potential target for therapy in PTEN-deficient CCA and other PTEN-deficient cancers.
Insights
Targeting the proteasome with inhibitors like bortezomib shows promise for treating cholangiocarcinoma (CCA) in patients with PTEN deficiency. This approach exploits a cancer cell
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Patient-derived xenografts (PDXs) and cells (PDCs) are valuable preclinical models for cancer research.
- Cholangiocarcinoma (CCA) remains a challenging cancer with limited effective treatments.
- Understanding the molecular drivers of CCA is crucial for developing targeted therapies.
Purpose of the Study:
- To identify novel therapeutic targets for cholangiocarcinoma (CCA).
- To investigate the role of PTEN deficiency in CCA cell survival and proliferation.
- To evaluate the efficacy of proteasome inhibitors in treating PTEN-deficient CCA.
Main Methods:
- Drug screening assay using PDX-derived cells (PDCs).
- Assessment of proteasome activity and protein synthesis in PTEN-deficient cells.
- Therapeutic evaluation in PDX, autochthonous mouse models, and patient samples.
- Mechanistic studies involving FOXO1, BACH1, and MAFF.
Main Results:
- Proteasome inhibitors were identified as promising drugs for CCA treatment.
- PTEN deficiency enhances protein synthesis and proteasome dependency in CCA cells.
- Bortezomib inhibited proliferation and survival of PTEN-deficient CCA cells.
- PTEN deficiency leads to FOXO1 nuclear translocation, repressing proteasome subunit gene transcription.
Conclusions:
- The PTEN-proteasome axis is a critical vulnerability in PTEN-deficient CCA.
- Targeting the proteasome with inhibitors represents a potential therapeutic strategy for PTEN-deficient CCA.
- This study highlights the importance of PTEN status in guiding CCA treatment decisions.
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