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Chromosome instability functions as a potential therapeutic reference by enhancing chemosensitivity to BCL-XL inhibitors in colorectal carcinoma

Acta Pharmacologica Sinica volume 45, pages 2420–2431 (2024)Cite this article

Abstract

Chromosome instability (CIN) and subsequent aneuploidy are prevalent in various human malignancies, influencing tumor progression such as metastases and relapses. Extensive studies demonstrate the development of chemoresistance in high-CIN tumors, which poses significant therapeutic challenges. Given the association of CIN with poorer prognosis and suppressed immune microenvironment observed in colorectal carcinoma (CRC), here we aimed to discover chemotherapeutic drugs exhibiting increased inhibition against high-CIN CRC cells. By using machine learning methods, we screened out two BCL-XL inhibitors Navitoclax and WEHI-539 as CIN-sensitive reagents in CRC. Subsequent analyses using a CIN-aneuploidy cell model confirmed the vulnerability of high-CIN CRC cells to these drugs. We further revealed the critical role of BCL-XL in the viability of high-CIN CRC cells. In addition, to ease the evaluation of CIN levels in clinic, we developed a three-gene signature as a CIN surrogate to predict prognosis, chemotherapeutic and immune responses in CRC samples. Our results demonstrate the potential value of CIN as a therapeutic target in CRC treatment and the importance of BCL-XL in regulating survival of high-CIN CRC cells, therefore representing a valuable attempt to translate a common trait of heterogeneous tumor cells into an effective therapeutic target.

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Fig. 1: CIN correlates with prognosis, disease progression and immune microenvironment in CRC samples.
Fig. 2: Drug screening of CIN-sensitive reagents in CRC samples.
Fig. 3: Chemosensitivity of high-CIN CRC cells to Navitoclax and WEHI-539 treatment.
Fig. 4: CIN sensitizes CRC cells to BCL-XL inhibition.
Fig. 5: Prognostic CIN-correlated gene signature predicts CIN level, immune infiltration and chemotherapeutic response in CRC samples.

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Acknowledgements

The authors are grateful for the support of the “Youth Talent Support Program” from Yangzhou University. This work was supported by the National Natural Science Foundation of China (81972251 to XF and 32170552 to YZ), Natural Science Research of Jiangsu Higher Education Institutions of China (23KJA310012 to XF and 21KJA180001 to YZ), and the Jiangsu Provincial Medical Key Discipline Cultivation Unit (JSDW202251).

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  1. These authors contributed equally: Xiao Fang, Wen-ying Yu

Authors and Affiliations

  1. Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, China

    Xiao Fang, Wen-ying Yu, Chun-miao Zhu, Nan Zhao, Wei Zhao, Ting-ting Xie, Li-jie Wei, Xi-ran Sun, Juan Xie & Ya Zhao

  2. Clinical Medical College, Yangzhou University, Yangzhou, 225009, China

    Xiao Fang

  3. Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou, 225001, China

    Xiao Fang, Wen-ying Yu, Chun-miao Zhu, Nan Zhao, Wei Zhao, Ting-ting Xie, Li-jie Wei, Xi-ran Sun, Juan Xie & Ya Zhao

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  1. Xiao Fang
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Contributions

XF and YZ designed the study. XF performed the bioinformatic analyses. WYY and YZ established the cell lines, performed cell viability, real-time PCR and flow cytometry analyses. WYY, TTX, and YZ performed the animal experiments. CMZ performed the chromosome spread assays with input of XRS and JX. NZ performed the caspase 3 activity assays. WZ and LJW constructed the plasmids and performed the Western blot analyses. XF, WYY, and YZ interpreted the data and drafted the manuscript.

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Correspondence to Ya Zhao.

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Fang, X., Yu, Wy., Zhu, Cm. et al. Chromosome instability functions as a potential therapeutic reference by enhancing chemosensitivity to BCL-XL inhibitors in colorectal carcinoma. Acta Pharmacol Sin 45, 2420–2431 (2024). https://doi.org/10.1038/s41401-024-01372-y

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