ALK fusion NSCLC oncogenes promote survival and inhibit NK cell responses via SERPINB4 expression

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genomics

Background:

• Anaplastic Lymphoma Kinase (ALK) fusions are oncogenic drivers in Non-Small Cell Lung Cancer (NSCLC).
• Treatment efficacy of ALK tyrosine kinase inhibitors (TKIs) can vary based on specific ALK fusion variants.
• Understanding the downstream signaling of different ALK fusions is crucial for personalized therapy.

Purpose of the Study:

• To investigate the transcriptomic and proteomic responses to varying ALK fusion variants.
• To identify common and isoform-specific signaling pathways driven by EML4-ALK, KIF5B-ALK, and TFG-ALK.
• To elucidate the role of Serpin B4 (SERPINB4) in ALK-driven NSCLC.

Main Methods:

• Development of inducible cell models expressing specific ALK fusion variants (EML4-ALK-V1, EML4-ALK-V3, KIF5B-ALK, TFG-ALK).
• Transcriptomic and proteomic analysis of cell models and patient-derived NSCLC cell lines.
• Investigation of transcriptional regulators (STAT3, NF-κB, AP1) of SERPINB4.

Main Results:

• Identified common and isoform-specific downstream responses to four ALK fusions.
• Observed an inflammatory signature with upregulated SERPINB4 in both engineered and patient-derived cells.
• Demonstrated that STAT3, NF-κB, and AP1 regulate SERPINB4 expression downstream of ALK fusions.

Conclusions:

• Upregulation of SERPINB4 promotes NSCLC cell survival.
• SERPINB4 inhibits natural killer cell-mediated cytotoxicity, impacting anti-tumor immunity.
• Targeting SERPINB4 in conjunction with ALK TKIs may offer a novel therapeutic strategy for NSCLC.