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BIOMARKER:

ALK F1174C

i
Other names: NBLST3, CD246, Anaplastic Lymphoma Kinase, Anaplastic Lymphoma Kinase (Ki-1), CD246 Antigen, Mutant Anaplastic Lymphoma Kinase, ALK, ALK Receptor Tyrosine Kinase, Anaplastic Lymphoma Receptor Tyrosine Kinase, ALK Tyrosine Kinase Receptor
Entrez ID:
2ms
A computational examination of the therapeutic advantages of fourth-generation ALK inhibitors TPX-0131 and repotrectinib over third-generation lorlatinib for NSCLC with ALK F1174C/L/V mutations. (PubMed, Front Mol Biosci)
This comparative study of the potential binding effects of fourth-generation inhibitors TPX-0131 and repotrectinib and third-generation inhibitor LOR for ALK F1174C/L/V mutations revealed the atomistic insights of the binding mechanism. These computational findings enable us to carry out further research for the clinical implementation of fourth-generation ALK inhibitors on ALK-positive NSCLC.
Journal
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ALK (Anaplastic lymphoma kinase)
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ALK positive • ALK rearrangement • ALK mutation • ALK F1174C • ALK F1174V
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Lorbrena (lorlatinib) • Augtyro (repotrectinib) • TPX-0131
2ms
ALK F1174S mutation impairs ALK kinase activity in EML4-ALK variant 1 and sensitizes EML4-ALK variant 3 to crizotinib. (PubMed, Front Oncol)
These findings highlight the complexity of drug selection when treating patients harboring resistance mutations and suggest that the F1174S mutation in EML4-ALK variant 1 is likely not a potent oncogenic driver. Additional oncogenic driver or other resistance mechanisms should be considered in the case of EML4-ALK variant 1 with F1174S mutation.
Journal
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ALK (Anaplastic lymphoma kinase) • EML4 (EMAP Like 4)
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EML4-ALK fusion • ALK fusion • ALK mutation • EML4-ALK variant 3 • ALK F1174C • EML4-ALK variant 1 • EML4-ALK F1174C
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Xalkori (crizotinib) • Lorbrena (lorlatinib)
9ms
Dynamic monitoring of circulating tumor DNA to analyze genetic characteristics and resistance profile of lorlatinib in ALK positive previously treated NSCLC. (PubMed, Thorac Cancer)
The dynamic changes of genomic characteristics during lorlatinib treatment revealed the mutation landscape of Chinese patients with NSCLC after ALK-TKI resistance, indicated that the resistance profile of lorlatinib were heterogeneous, which laid the foundation for subsequent treatment to overcome lorlatinib resistance.
Journal • Circulating tumor DNA
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ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • DNMT3A (DNA methyltransferase 1) • GNAS (GNAS Complex Locus) • ERCC3 (ERCC Excision Repair 3, TFIIH Core Complex Helicase Subunit)
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ALK positive • ALK mutation • ALK G1202R • ALK F1174C • ALK L1196M • ALK D1203N
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Lorbrena (lorlatinib)
2years
Real-world circulating tumor DNA analysis depicts resistance mechanism and clonal evolution in ALK inhibitor-treated lung adenocarcinoma patients. (PubMed, ESMO Open)
Sequential postprogression plasma profiling revealed that increased lines of ALK inhibitors can accelerate the accumulation of ALK resistance mutations and may lead to treatment-refractory compound ALK mutations. The selection for optimal first-line TKI is very important to achieve a more efficacious long-term strategy and prevent the emergence of on-target resistance, which may provide guidance for clinical decision making.
Journal • Real-world evidence • Circulating tumor DNA
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • EML4 (EMAP Like 4) • MYCN (MYCN Proto-Oncogene BHLH Transcription Factor)
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TP53 mutation • ALK positive • ALK fusion • ALK mutation • ALK G1202R • EML4-ALK L1196M • ALK F1174C • ALK L1196M • EML4-ALK G1202R • ALK D1203N • EML4-ALK F1174C
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Xalkori (crizotinib) • Alecensa (alectinib) • Lorbrena (lorlatinib)
over2years
A Novel Sequentially Evolved EML4-ALK Variant 3 G1202R/S1206Y Double Mutation In Cis Confers Resistance to Lorlatinib: A Brief Report and Literature Review. (PubMed, JTO Clin Res Rep)
Here, we report, for the first time, a novel, sequentially-evolved EML4-ALK variant 3 G1202R/S1206Y double mutation in cis detected in a patient with ALK-positive NSCLC after disease progression on sequential crizotinib, alectinib, and then lorlatinib. Three-dimensional computer modeling of this double mutation and other G1202R-based double mutations with lorlatinib (ALK G1202R/L1196M, ALK G1202R/F1174C, ALK G1202R/l1198F, ALK G1202R/G1269A) were provided to reveal how these double mutations may confer resistance to lorlatinib through diverse steric hindrances in the ALK kinase domain. In addition, we performed a comprehensive literature review on published acquired double or triple ALK mutations that are resistant to lorlatinib from both patient samples and in vitro mutagenesis experiments.
Review • Journal
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ALK (Anaplastic lymphoma kinase) • EML4 (EMAP Like 4)
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ALK positive • ALK mutation • EML4-ALK variant 3 • ALK G1202R • ALK G1269A • EML4-ALK L1196M • ALK F1174C • ALK L1196M • ALK S1206Y • EML4-ALK G1202R • EML4-ALK G1269A • EML4-ALK F1174C • EML4-ALK S1206Y
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Xalkori (crizotinib) • Alecensa (alectinib) • Lorbrena (lorlatinib)
over2years
[VIRTUAL] Clinical utility of ctDNA for detection of EGFR, ALK, BRAFV600E alterations and resistance mutations in patients with NSCLC at failure to targeted therapy (ESMO 2021)
In samples from EGFRm ex19/21 pts treated with 1st/2nd generation (gen.) TKI (n=51), the T790M mutation was detected in 27%; in those from pts treated with osimertinib (n=15), the C797S rate was 13%. In ALKr pts treated with crizotinib (n=17), ≥1 ALK resistance mutations were found in 12% (1 G1269A+F1174L, 1 G1202R), after 2nd gen. (n=16) in 31% (3 G1202R, 1 D1203N+F1174C, 1 T1151R) and after lorlatinib (n=16) in 13% (2 G1202R)... ctDNA is feasible in pts with NSCLC harbouring EGFRm, ALKr, BRAFV600Em for detecting driver and resistance GAs at PD, providing clinical informative for treatment selection at TKI failure in 22% of cases. Outcomes of the following therapies based on ctDNA will be presented at the congress.
Clinical • Circulating tumor DNA
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • CTNNB1 (Catenin (cadherin-associated protein), beta 1)
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BRAF V600E • EGFR mutation • BRAF V600 • EGFR T790M • ALK rearrangement • EGFR C797S • ALK G1202R • ALK G1269A • ALK F1174C • ALK F1174L + ALK G1202R • ALK D1203N • ALK T1151R
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InVisionFirst®-Lung
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Mekinist (trametinib) • Xalkori (crizotinib) • Tagrisso (osimertinib) • Tafinlar (dabrafenib) • Lorbrena (lorlatinib)
3years
Activated ALK Cooperates with N-Myc via Wnt/β-catenin Signaling to Induce Neuroendocrine Prostate Cancer. (PubMed, Cancer Res)
We previously identified the first case of ALK F1174C-activating mutation in a patient with de novo NEPC who responded to the ALK inhibitor alectinib...These findings point to a role for ALK signaling in NEPC and the potential of co-targeting the ALK and Wnt/β-catenin pathways in ALK-driven tumors. Activated ALK and N-Myc are well known drivers in neuroblastoma development, suggesting potential similarities and opportunities to elucidate mechanisms and therapeutic targets in NEPC and vice versa.
Journal
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ALK (Anaplastic lymphoma kinase) • MYCN (MYCN Proto-Oncogene BHLH Transcription Factor)
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ALK mutation • MYCN amplification • ALK F1174C
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Alecensa (alectinib)