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Case Report: A Novel Non-Reciprocal ALK Fusion: ALK-GCA and EML4-ALK Were Identified in Lung Adenocarcinoma, Which May Respond to Alectinib Adjuvant-Targeted Therapy.

ABSTRACT: Anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancers (NSCLCs) have favorable and impressive response to ALK tyrosine kinase inhibitors (TKIs). However, ALK rearrangement had approximately 90 distinct fusion partners. Patients with different ALK fusions might have distinct responses to different-generation ALK-TKIs. In this case report, we identified a novel non-reciprocal ALK fusion: ALK-grancalcin (GCA) (A19: intragenic) and EML4-ALK (E20: A20) by next-generation sequencing (NGS) in a male lung adenocarcinoma patient who was staged as IIIB-N2 after surgery. After a multidisciplinary discussion, the patient received alectinib adjuvant targeted therapy and postoperative radiotherapy (PORT). He is currently in good condition, and disease-free survival (DFS) has been 20 months so far, which has been longer than the median survival time of IIIB NSCLC patients. Our study extended the spectrum of ALK fusion partners in ALK + NSCLC, and we reported a new ALK fusion: ALK-GCA and EML4-ALK and its sensitivity to alectinib firstly in lung cancer. It is vital for clinicians to detect fusion mutations of patients and report timely the newfound fusions and their response to guide treatment.

SUBMITTER: Zhai X

PROVIDER: S-EPMC8767047 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Lung cancers bearing oncogenic EML4-ALK fusions respond to targeted tyrosine kinase inhibitors (TKIs; e.g., alectinib), with variation in the degree of shrinkage and duration of treatment (DOT). However, factors that control this response are not well understood. While the contribution of the immune system in mediating the response to immunotherapy has been extensively investigated, less is known regarding the contribution of immunity to TKI therapeutic responses. We previously demonstrated a positive association of a TKI-induced interferon gamma (IFNγ) transcriptional response with DOT in EGFR-mutant lung cancers. Herein, we used three murine models of EML4-ALK lung cancer to test the role for host immunity in the alectinib therapeutic response. The cell lines (EA1, EA2, EA3) were propagated orthotopically in the lungs of immunocompetent and immunodeficient mice and treated with alectinib. Tumor volumes were serially measured by μCT and immune cell content was measured by flow cytometry and multispectral immunofluorescence. Transcriptional responses to alectinib were assessed by RNAseq and secreted chemokines were measured by ELISA. All cell lines were similarly sensitive to alectinib in vitro and as orthotopic tumors in immunocompetent mice, exhibited durable shrinkage. However, in immunodeficient mice, all tumor models rapidly progressed on TKI therapy. In immunocompetent mice, EA2 tumors exhibited a complete response, whereas EA1 and EA3 tumors retained residual disease that rapidly progressed upon termination of TKI treatment. Prior to treatment, EA2 tumors had greater numbers of CD8+ T cells and fewer neutrophils compared to EA1 tumors. Also, RNAseq of cancer cells recovered from untreated tumors revealed elevated levels of CXCL9 and 10 in EA2 tumors, and higher levels of CXCL1 and 2 in EA1 tumors. Analysis of pre-treatment patient biopsies from ALK+ tumors revealed an association of neutrophil content with shorter time to progression. Combined, these data support a role for adaptive immunity in durability of TKI responses and demonstrate that the immune cell composition of the tumor microenvironment is predictive of response to alectinib therapy.

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Case Report: A Novel Non-Reciprocal ALK Fusion: ALK-GCA and EML4-ALK Were Identified in Lung Adenocarcinoma, Which May Respond to Alectinib Adjuvant-Targeted Therapy.

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