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

Fu-jing Ge1, Xiao-yang Dai1, Yao Qiu2, Xiang-ning Liu1, Chen-ming Zeng3, Xiao-yuan Xu4, Yi-dan Chen2, Hong Zhu1, Qiao-jun He1,5, Ren-hua Gai6, Sheng-lin Ma2,5, Xue-qin Chen2,5, Bo Yang1,7
1 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
2 Department of Thoracic Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou Cancer Hospital, Hangzhou 310002, China
3 Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310000, China
4 China Pharmaceutical University, Nanjing 210009, China
5 Cancer Center, Zhejiang University, Hangzhou 310058, China
6 Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
7 School of Medicine, Hangzhou City University, Hangzhou 310015, China
Correspondence to: Sheng-lin Ma:, Xue-qin Chen:, Bo Yang:,
DOI: 10.1038/s41401-024-01230-x
Received: 4 September 2023
Accepted: 18 January 2024
Advance online: 15 February 2024


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.

Keywords: EML4-ALK positive NSCLC; ALK tyrosine kinase inhibitors; drug resistance; patient-derived models; prognostic biomarkers

Article Options

Download Citation

Cited times in Scopus