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Anticancer Drugs
2022 Nov 01;3310:1182-1185. doi: 10.1097/CAD.0000000000001363.
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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
.
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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.
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