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Antitumor activity and mechanism of resistance of the novel HDAC and PI3K dual inhibitor CUDC-907 in pancreatic cancer

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Abstract

Purpose

Pancreatic cancer is a highly malignant disease with an extremely poor prognosis. The benefit of chemotherapy treatment for pancreatic cancer is very limited. Therefore, new therapeutic targets and approaches are urgently needed for this deadly disease. Multi-target therapy is a potential and feasible treatment strategy. Given the important roles that histone deacetylases (HDACs) and phosphoinositide-3-kinase (PI3K) play in pancreatic cancer, we investigated the antitumor activity and mechanism of novel HDAC and PI3K dual inhibitor CUDC-907 in pancreatic cancer.

Methods and results

MTT assay and flow cytometric analysis were used to examine the in vitro antitumor activity of CUDC-907. A BxPC-3-derived xenograft mouse model was used to determine CUDC-907 in vivo efficacy. The TUNEL assay as used to determine apoptosis in tumors in vivo post CUDC-907 treatment. Western blots were used to determine the effect of CUDC-907 on protein levels. Our results show that CUDC-907 decreased viable cells and induced cell death in a concentration-dependent manner. Furthermore, CUDC-907 showed promising in vivo antitumor activity in the BxPC-3-derived xenograft mouse model while exhibiting tolerable toxicity. Furthermore, long-term treatment with CUDC-907 induced phosphorylation of AKT, S6 (ribosomal protein S6), and ERK (extracellular regulated protein kinase), and inhibition of PI3K (phosphatidylinositol 3-kinase), mTOR (mammalian target of rapamycin), or ERK significantly enhanced CUDC-907-induced cell death in pancreatic cell lines.

Conclusion

Taken together, these findings support the clinical development of CUDC-907 for the treatment of pancreatic cancer and identify compensatory activation of mTOR and MEK/ERK as a possible mechanism of resistance to CUDC-907.

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All data generated and analyzed during this study are included in this published article.

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Acknowledgements

This study was supported by the Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University.

Funding

This study was supported by the School of Life Sciences of Jilin University a grant from the National Natural Science Foundation of China (NSFC 81800154).

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Authors and Affiliations

  1. Key Laboratory for Molecular Enzymology and Engineering, National Engineering Laboratory for AIDS Vaccine, The Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, Jilin, China

    Shuang Liu, Shoujing Zhao, Yang Dong, Tingting Wang, Xiaojia Niu & Guan Wang

  2. Department of Rehabilitation, School of Nursing, Jilin University, Changchun, China

    Lijing Zhao

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  1. Shuang Liu
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  2. Shoujing Zhao
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  3. Yang Dong
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  4. Tingting Wang
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  5. Xiaojia Niu
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  6. Lijing Zhao
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  7. Guan Wang
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Contributions

Conceptualization, GW; in vitro experiments, SL, YD, and TW; in vivo experiments, LZ and XN; data analysis, SL, SZ, and GW; supervision, SZ and GW; draft preparation and funding acquisition, GW.

Corresponding author

Correspondence to Guan Wang.

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The authors declare no competing interests.

Ethics approval

The animal study was conducted following internationally recognized guidelines and was approved by the Animal Research Committee of Norman Bethune College of Medicine, Jilin University.

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Liu, S., Zhao, S., Dong, Y. et al. Antitumor activity and mechanism of resistance of the novel HDAC and PI3K dual inhibitor CUDC-907 in pancreatic cancer. Cancer Chemother Pharmacol 87, 415–423 (2021). https://doi.org/10.1007/s00280-020-04210-0

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  • DOI: https://doi.org/10.1007/s00280-020-04210-0

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