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Inflammation-related molecular signatures involved in the anticancer activities of brigatinib as well as the prognosis of EML4-ALK lung adenocarcinoma patient

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Although ALK tyrosine kinase inhibitors (ALK-TKIs) have shown remarkable benefits in EML4-ALK positive NSCLC patients compared to conventional chemotherapy, the optimal sequence of ALK-TKIs treatment remains unclear due to the emergence of primary and acquired resistance and the lack of potential prognostic biomarkers. In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. Based on the patient-derived models and clinical responses of the patient, we found that crizotinib might inhibit proliferation of EML4-ALK positive tumors resistant to alectinib and lorlatinib. In addition, NSCLC patients harboring the G1269A mutation, which was identified in alectinib, lorlatinib and crizotinib-resistant NSCLC, showed responsiveness to brigatinib and ceritinib. Transcriptomic analysis revealed that brigatinib suppressed the activation of multiple inflammatory signaling pathways, potentially contributing to its anti-tumor activity. Moreover, we constructed a prognostic model based on the expression of IL6, CXCL1, and CXCL5, providing novel perspectives for predicting prognosis in EML4-ALK positive NSCLC patients. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.

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Fig. 1: The prediction of clinical responses based on the EML4-ALK positive NSCLC PDC, PDO and PDX models.
Fig. 2: Brigatinib inhibits the expression of inflammation-related genes.
Fig. 3: Brigatinib inhibits the activation of inflammation-related pathways.
Fig. 4: PPI network analysis revealed hub genes inhibited by brigatinib.
Fig. 5: Construction and evaluation of the prognostic model based on the expression levels of IL6, CXCL1 and CXCL5.
Fig. 6: Brigatinib suppresses the expression of IL6, CXCL1, and CXCL5 in PDC models.
Fig. 7: Inflammation-related pathways and factors are associated with resistance to ALK-TKIs.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (U21A20420) and the Science and Technology Development Project of Hangzhou (202204A08). We thank Dr. Jian-ming Zeng (University of Macau) and all the members of his bioinformatics team, biotrainee, for generously sharing their experience and codes. The use of the biorstudio high-performance computing cluster (http://biotrainee.vip:9903/) at Biotrainee and the Shanghai HS Biotech Co., Ltd for conducting the research reported in this paper.

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  1. These authors contributed equally: Fu-jing Ge, Xiao-yang Dai, Yao Qiu

Authors and Affiliations

  1. Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    Fu-jing Ge, Xiao-yang Dai, Xiang-ning Liu, Hong Zhu, Qiao-jun He & Bo Yang

  2. Department of Thoracic Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou Cancer Hospital, Hangzhou, 310002, China

    Yao Qiu, Yi-dan Chen, Sheng-lin Ma & Xue-qin Chen

  3. Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310000, China

    Chen-ming Zeng

  4. China Pharmaceutical University, Nanjing, 210009, China

    Xiao-yuan Xu

  5. Cancer Center, Zhejiang University, Hangzhou, 310058, China

    Qiao-jun He, Sheng-lin Ma & Xue-qin Chen

  6. Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    Ren-hua Gai

  7. School of Medicine, Hangzhou City University, Hangzhou, 310015, China

    Bo Yang

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Contributions

FJG, XYD, and YQ were responsible for experiment design, biological information analysis, and manuscript writing. XNL and CMZ was responsible for results description, handling of pictures and tables. XYX was responsible for clinical samples required for research. YDC and RHG assisted animal modeling and revised the manuscript. HZ and QJH were responsible for language embellishment and manuscript writing. SLM, XQC, and BY were responsible for the research design, supervising the study, and editing manuscript.

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Correspondence to Sheng-lin Ma, Xue-qin Chen or Bo Yang.

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Ge, Fj., Dai, Xy., Qiu, Y. et al. Inflammation-related molecular signatures involved in the anticancer activities of brigatinib as well as the prognosis of EML4-ALK lung adenocarcinoma patient. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01230-x

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