Reference Detail

Ref Type

Journal Article

PMID

(38360931)

Authors

Ge FJ, Dai XY, Qiu Y, Liu XN, Zeng CM, Xu XY, Chen YD, Zhu H, He QJ, Gai RH, Ma SL, Chen XQ, Yang B

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Acta pharmacologica Sinica			2024 Feb 15		Acta Pharmacol Sin

URL

Abstract Text

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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4 - ALK ALK G1269A	lung adenocarcinoma	sensitive	Brigatinib	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, Alunbrig (brigatinib) treatment inhibited viability of patient-derived organoids of lung adenocarcinoma harboring EML4-ALK and ALK G1269A in culture and resulted in tumor shrinkage in a patient-derived xenograft (PDX) model (PMID: 38360931).	38360931
EML4 - ALK ALK G1269A	lung adenocarcinoma	sensitive	Ceritinib	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, Zykadia (ceritinib) treatment inhibited viability of patient-derived organoids of lung adenocarcinoma harboring EML4-ALK and ALK G1269A in culture and resulted in tumor shrinkage in a patient-derived xenograft (PDX) model (PMID: 38360931).	38360931
EML4 - ALK ALK G1269A	lung adenocarcinoma	predicted - resistant	Crizotinib	Case Reports/Case Series	Actionable	In a clinical case study, ALK G1269A was identified at progression on Xalkori (crizotinib) in a patient with lung adenocarcinoma harboring EML4-ALK (PMID: 38360931).	38360931