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Proteomics analysis of histone deacetylase inhibitor-resistant solid tumors reveals resistant signatures and potential drug combinations

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Histone deacetylase inhibitors (HDACis) are important drugs for cancer therapy, but the indistinct resistant mechanisms of solid tumor therapy greatly limit their clinical application. In this study we conducted HDACi-perturbated proteomics and phosphoproteomics analyses in HDACi-sensitive and -resistant cell lines using a tandem mass tag (TMT)-based quantitative proteomic strategy. We found that the ribosome biogenesis proteins MRTO4, PES1, WDR74 and NOP16 vital to tumorigenesis might regulate the tumor sensitivity to HDACi. By integrating HDACi-perturbated protein signature with previously reported proteomics and drug sensitivity data, we predicted and validated a series of drug combination pairs potentially to enhance the sensitivity of HDACi in diverse solid tumor. Functional phosphoproteomic analysis further identified the kinase PDK1 and ROCK as potential HDACi-resistant signatures. Overall, this study reveals the potential HDACi-resistant signatures and may provide promising drug combination strategies to attenuate the resistance of solid tumor to HDACi.

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Fig. 1: TMT-based proteomics and phosphoproteomics analysis of the HDACi-sensitive and resistant cell lines treated with SAHA.
Fig. 2: GSEA analysis of proteome in the HDACi-sensitive and resistant cell lines treated with SAHA.
Fig. 3: Proteomics analysis of ribosome biogenesis and MYC target in the sensitive and resistant cell lines treated with SAHA.
Fig. 4: The prediction and validation of potential combined drugs with HDACi based on proteomics data.
Fig. 5: Functional phosphoproteomics analysis of differential phosphorylation sites in the sensitive and resistant cells after SAHA treatment.
Fig. 6: Kinase analysis in the sensitive and resistant cells after SAHA treatment.

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Data availability

All mass spectrometry raw data have been deposited to the iProX Consortium with Project ID: IPX0006624000.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (32071432, 32171434, 82272943, 32322048), the Youth Science and Technology Talents in Shanghai Sail Plan of China (21YF1456000), Young Elite Scientists Sponsorship Program by CAST (2022QNRC001), Shanghai Rising-Star Program (22QA1411100), the Youth Innovation Promotion Association (CAS2021276) and the Sanofi Scholarship Program, Shanghai Committee of Science and Technology, China (21Y11913400), Guangdong High-level New R&D Institute, China (2019B090904008), Guangdong High-level Innovative Research Institute, China (2021B0909050003).

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Author notes

  1. These authors contributed equally: Bing-bing Hao, Ke Ma, Jun-yu Xu, Ru-feng Fan

Authors and Affiliations

  1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Bing-bing Hao, Jun-yu Xu, Ru-feng Fan, Xing-long Jia, Lin-hui Zhai & Min-jia Tan

  2. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Ke Ma & Min-jia Tan

  3. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China

    Jun-yu Xu, Lin-hui Zhai & Min-jia Tan

  4. University of Chinese Academy of Sciences, Beijing, 100049, China

    Ru-feng Fan & Min-jia Tan

  5. Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China

    Wen-si Zhao & Dong Xie

  6. Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China

    Xing-long Jia

  7. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea

    SangKyu Lee

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Contributions

MJT, BBH, DX and JYX conceived and supervised the project; BBH and JYX performed all the proteomics experiments; BBH, KM, JYX and RFF analyzed the data and performed the biological experiments; XLJ assisted with part of experiments; WSZ, LHZ and SL assisted with part of data analysis; BBH, KM, JYX and RFF wrote the manuscript; MJT and DX revised the manuscript. All authors approved the final version of the manuscript.

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Correspondence to Jun-yu Xu, Dong Xie or Min-jia Tan.

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Hao, Bb., Ma, K., Xu, Jy. et al. Proteomics analysis of histone deacetylase inhibitor-resistant solid tumors reveals resistant signatures and potential drug combinations. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01236-5

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