Click
here to close Hello! We notice that
you are using Internet Explorer, which is not supported by Echinobase
and may cause the site to display incorrectly. We suggest using a
current version of Chrome,
FireFox,
or Safari.
Anticancer Drugs
2022 Nov 01;3310:1182-1185. doi: 10.1097/CAD.0000000000001363.
Show Gene links
Show Anatomy links
A novel intergenic region ALK fusion is targetable by alectinib in a non-small cell lung cancer patient with brain metastasis.
Cheng W
,
Qian C
,
Zhang H
,
Meng Q
,
Yin JC
,
Fang S
.
???displayArticle.abstract???
Anaplastic lymphoma kinase ( ALK ) rearrangement defines a unique nonsmall cell lung cancer (NSCLC) molecular subtype, of which the patients could potentially benefit from anti- ALK therapies. So far, the outcomes of the canonical echinoderm microtubule-associated protein-like ( EML-ALK ) patients subjected to ALK inhibitors are well established. However, given the increasing complexity of ALK fusion partners, as detected by high-throughput sequencing, the responses of those with rare ALK fusion events remain to be explored. Here, we report a lung adenocarcinoma patient with brain metastasis harboring an ARHGAP5 downstream intergenic region ALK fusion, as detected by using DNA-based next-generation sequencing, who experienced a partial response to alectinib treatment. While whole- transcriptome RNA sequencing (RNA-seq) failed to identify potential ALK fusion transcripts, subsequent targeted deep RNA-seq revealed the expression of EML4-ALK transcripts in the tumor tissue. Given the increasing application of the ALK-tyrosine kinase inhibitors (TKIs), it is extremely crucial to define the patients who could be suitable for this treatment in clinic. The present case has provided supporting evidence that noncanonical ALK rearrangements on the genomic level are often functionally relevant and targetable by ALK-TKI, particularly in cases with sub-optimal quantity and quality for RNA validation.
Fig. 1. Representative radiologic images before and after surgery. Brain metastases in the left parietal lobe before surgery (a) and after surgery (b).
Fig. 2. Representative radiologic images and treatment timeline of the patient. The red arrows indicate the primary tumor lesions in the lung before surgery (a), after surgery (b), at disease progression (c) and regression after alectinib treatment (d).
Fig. 3. A novel intergenic region between ARHGAP5 and RNU6-7 fused to the ALK kinase domain was identified. (a) The schematic of the novel ALK fusion. The breakpoints on the intergenic region and ALK are located on chr14:32663458 and chr2:29446463, respectively. The snapshots of the ALK fusion tested by DNA-based NGS (b) and RNA-seq (c) on Intergrative Genomics Viewer. The dashed lines in green indicated the breakpoints. The colored letters indicate the mismatched bases around the breakpoints due to the ALK rearrangement. ALK, anaplastic lymphoma kinase; NGS, next-generation sequencing.
Fei,
A Novel Intergenic Region between CENPA and DPYSL5-ALK Exon 20 Fusion Variant Responding to Crizotinib Treatment in a Patient with Lung Adenocarcinoma.
2019, Pubmed
Fei,
A Novel Intergenic Region between CENPA and DPYSL5-ALK Exon 20 Fusion Variant Responding to Crizotinib Treatment in a Patient with Lung Adenocarcinoma.
2019,
Pubmed
Feng,
The clinical responses of TNIP2-ALK fusion variants to crizotinib in ALK-rearranged lung adenocarcinoma.
2019,
Pubmed
Jiang,
GCC2-ALK as a targetable fusion in lung adenocarcinoma and its enduring clinical responses to ALK inhibitors.
2018,
Pubmed
Kang,
Complex ALK Fusions Are Associated With Better Prognosis in Advanced Non-Small Cell Lung Cancer.
2020,
Pubmed
,
Echinobase
Li,
Intergenic Breakpoints Identified by DNA Sequencing Confound Targetable Kinase Fusion Detection in NSCLC.
2020,
Pubmed
Li,
Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC.
2021,
Pubmed
Lin,
Comparison of ALK detection by FISH, IHC and NGS to predict benefit from crizotinib in advanced non-small-cell lung cancer.
2019,
Pubmed
Lin,
Impact of EML4-ALK Variant on Resistance Mechanisms and Clinical Outcomes in ALK-Positive Lung Cancer.
2018,
Pubmed
Peters,
Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer.
2017,
Pubmed
Rosenbaum,
Genomic heterogeneity of ALK fusion breakpoints in non-small-cell lung cancer.
2018,
Pubmed
Soda,
Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.
2007,
Pubmed
,
Echinobase
Solomon,
ALK gene rearrangements: a new therapeutic target in a molecularly defined subset of non-small cell lung cancer.
2009,
Pubmed
,
Echinobase
Zhang,
CUX1-ALK, a Novel ALK Rearrangement That Responds to Crizotinib in Non-Small Cell Lung Cancer.
2018,
Pubmed
Zhang,
A Novel Linc00308/D21S2088E Intergenic Region ALK Fusion and Its Enduring Clinical Responses to Crizotinib.
2020,
Pubmed
Zhao,
Clinicopathological Features of ALK Expression in 9889 Cases of Non-small-Cell Lung Cancer and Genomic Rearrangements Identified by Capture-Based Next-Generation Sequencing: A Chinese Retrospective Analysis.
2019,
Pubmed
