Molecular inhibitory mechanism study on the potent inhibitor brigatinib against four crizotinib‐resistant ALK mutations

Tu, Jing; Song, Li Ting; Liu, Rui Rui; Zhai, Hong Lin; Wang, Juan; Zhang, Xiao Yun

doi:10.1002/jcb.27412

Cited by 7 publications

(3 citation statements)

References 57 publications

(102 reference statements)

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“…Patient with ALK E1129V, F1174C, F1174L, F1174V, I1171T, and G1269A responded to brigatinib lasting 10 months and brigatinib was discontinued when her general condition worsened, at which time liquid biopsy detected the accumulation of EML4-ALK variant 1 and ALK F1174C. ALK F1174C is reported to be resistant to crizotinib but sensitive to brigatinib (6,9). However, we noticed the ALK F1174C might be the resistance mutation of brigatinib.…”

Section: Discussionmentioning

confidence: 78%

Durable clinical response to ALK tyrosine kinase inhibitors in ALK-rearranged non-small cell lung cancer: a case report

Huang¹,

Dai²,

Ding³

2022

Transl Cancer Res TCR

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Background: Anaplastic lymphoma kinase (ALK) rearrangement is a key oncogenic driver promoting the expression of ALK protein in non-small-cell lung cancer (NSCLC). ALK tyrosine kinase inhibitors (TKIs) have significantly improved survival benefits. However, the emergence of drug resistance limits their clinical benefits.Case Description: We herein report a patient benefited from the sequential use of ALK TKIs (crizotinib, brigatinib, and lorlatinib) based on liquid biopsy testing. A female patient with stage IIIB NSCLC had a progression after chemotherapy and sequential radiotherapy. DNA-based next-generation sequencing (NGS) assay was performed in bronchoscopic biopsy tissue sample, demonstrating EML4-ALK (E13:A20) rearrangement. Crizotinib was administered, and partial response (PR) was achieved with a progressionfree survival (PFS) of 8 months. Brigatinib was used when NGS simultaneously identified the six mutations ALK E1129V, F1174C, F1174L, F1174V, I1171T, and G1269A, with the retention of EML4-ALK. The best overall response of brigatinib was a stable disease, and the PFS was 10 months. Lorlatinib was prescribed at brigatinib progression with five out of the six ALK mutations undetected. The patient took alectinib after lorlatinib resistance with ALK L1196M. The overall survival was four years.Conclusions: EML4-ALK rearrangement was detected after chemotherapy treatment in an NSCLC patient with a remarkable therapeutic response with ALK TKIs based on liquid biopsy testing. We also revealed crizotinib acquired resistance mediated by multiple mutations ALK E1129V, F1174C, F1174L, F1174V, I1171T, and G1269A, while five mutations were undetected after brigatinib treatment. ALK F1174C may be the resistant mutation of brigatinib.

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Section: Discussionmentioning

confidence: 78%

Durable clinical response to ALK tyrosine kinase inhibitors in ALK-rearranged non-small cell lung cancer: a case report

Huang¹,

Dai²,

Ding³

2022

Transl Cancer Res TCR

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“…Furthermore, in 2020 it was approved as first-line treatment for ALK-positive metastatic NSCLC patients [100][101][102]. Brigatinib also inhibits ROS1 fusions and EGFR mutation (L858R) and has a remarkable activity on the central nervous system [102,103]. According to the clinical data, brigatinib is active against all the 17 known resistance mutations to the ALK gene, including G1202R and L1196M [104,105].…”

Section: Describing Mechanisms Of Resistance In the First Second And Third Generation Of Alk Tkimentioning

confidence: 99%

An insight into lung cancer: a comprehensive review exploring ALK TKI and mechanisms of resistance

Pătcaș

Chiș

Militaru

et al. 2021

Bosn J of Basic Med Sci

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Implementation of precision medicine in lung cancer has benefited from intense research in the past years, developing subsequently an improved quality of life and increased overall survival of the patients. Targeted therapy has become one of the most important therapeutic innovations for the non-small cell lung cancer (NSCLC) category with anaplastic lymphoma kinase (ALK) gene rearrangement. The aim of this review is to provide a through overview of the main molecules of ALK tyrosine kinase inhibitors (TKI) with their general and particular mechanisms of resistance, the main methods of ALK gene detection, each with advantages and limits and the future perspectives currently under research which try to overcome the mechanisms of resistance. We have used two of the most reliable medical databases EMBASE and PubMed to properly select the latest and the most relevant articles for this topic. Encouraged by the promising results, the clinical practice was enriched by the approval of tyrosine kinase inhibitor molecules, three generations being developed, each one with more powerful agents than the previous ones. Unfortunately, the resistance to TKI eventually occurs and it may be induced by several mechanisms, either known or unknown. Crizotinib was the most intensely studied TKI , becoming the first molecule approved into clinical practice and although four other drugs have been broadly used (alectinib, ceritinib, brigatinib and lorlatinib) it seems that even the most recently developed one remains imperfect due to the resistance mutations that developed. There are two types of resistance generally described for the entire class and for the particular drugs, but half of them remain unknown Read more in PDF.

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“…The S1189C mutation in the ALK kinase domain has not been reported in previous studies, nor is it recorded in any publicly available databases of oncogenes (such as COSMIC and ClinVar). Although brigatinib ( Tu et al, 2019 ), alectinib ( Zhang et al, 2016 ), and lorlatinib ( Syed, 2019 ), as FDA-approved ALK inhibitors, are effective against the F1174L mutation, previous reports have shown that the ALK gene compound mutation is resistant to almost all ALK-TKI inhibitors ( Gainor et al, 2016 ; Takahashi et al, 2020 ; Salifu et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Primary resistance to first- and second-generation ALK inhibitors in a non-small cell lung cancer patient with coexisting ALK rearrangement and an ALK F1174L-cis-S1189C de novo mutation: A case report

Zhao

Fan

et al. 2022

Front. Pharmacol.

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The effectiveness of the tyrosine kinase inhibitor ALK (TKI) for non-small cell lung cancer has been confirmed. However, resistance to ALK-TKIs seems inevitable. Mutations in the ALK kinase domain have been reported as an important mechanism of acquired resistance to ALK therapy. However, patients with de novo ALK kinase domain mutations and ALK rearrangements who were not treated with ALK inhibitors have rarely been reported. Here, we report a case of primary drug resistance to first- and second-generation ALK inhibitors in a NSCLC patient with ALK-rearrangement. The next-generation sequencing test of the pathological biopsy showed that the de novo ALK kinase domain mutation F1174L-cis-S1189C may be the cause of primary drug resistance.

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Molecular inhibitory mechanism study on the potent inhibitor brigatinib against four crizotinib‐resistant ALK mutations

Cited by 7 publications

References 57 publications

Durable clinical response to ALK tyrosine kinase inhibitors in ALK-rearranged non-small cell lung cancer: a case report

Durable clinical response to ALK tyrosine kinase inhibitors in ALK-rearranged non-small cell lung cancer: a case report

An insight into lung cancer: a comprehensive review exploring ALK TKI and mechanisms of resistance

Primary resistance to first- and second-generation ALK inhibitors in a non-small cell lung cancer patient with coexisting ALK rearrangement and an ALK F1174L-cis-S1189C de novo mutation: A case report

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