Abstract
The development of targeted therapies that inhibit cancer-driving oncogenes has improved outcomes of patients diagnosed with lung adenocarcinoma (LUAD). In contrast, patients diagnosed with lung squamous cell carcinoma (LUSC) suffer worse survival outcomes and lack effective targeted treatment options. Identification of molecular drivers of LUSC to support development of targeted treatments is urgently needed. Addressing this need, the current report introduces the novel cancer gene SLIT- and NTRK-like family member 3 (SLITRK3) and its role in activating the neurotrophic receptor tyrosine kinase 3 (NTRK3) in LUSC cells. Multiple genome-wide data sets from patient samples were produced by us or downloaded from public databases to analyze tumor gene copy number aberrations, mRNA expression and associated survival outcomes. An accompanying mechanistic study employed LUSC cell lines and multiple methods, including in situ immunofluorescence, sphere-formation assay, and fluorescence-activated cell sorting analysis of the CD133-positive cell fraction. Altogether, the results indicate that gene amplification and consequent high expression of SLITRK3 in LUSC is associated with worse outcomes and induces SLITRK3-dependent activation of NTRK3 to promote a cancer stem cell phenotype that is inhibited by existing NTRK-targeted inhibitors. Based on a recent literature search, this is the first report of a mechanistic role for SLITRK3 in cancer.
Highlights
Lung cancer is the leading cause of cancer-related death in the United States [1]
SLIT- and neurotrophic receptor tyrosine kinase (NTRK)-like family member 3 (SLITRK3) is frequently amplified in lung squamous cell carcinoma (LUSC) We first encountered SLITRK3 in exploratory analysis of 27 tissue samples from patients with advanced Non-small cell lung cancer (NSCLC) using high-density array comparative genomic hybridization
Our findings indicate that neurotrophic receptor tyrosine kinase 3 (NTRK3) activation dependent on aberrant SLITRK3 expression due to SLITRK3 amplification in LUSC may be targeted by currently available NTRK inhibitors
Summary
Lung cancer is the leading cause of cancer-related death in the United States [1]. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases, with the majority of patients presenting with incurable advanced stage disease. The 5year overall survival rate of advanced NSCLC has greatly improved due to the development of immune checkpoint inhibitors and targeted therapies that inhibit known cancer-driving oncogenes [2,3,4]. Carcinogenesis and cancer progression are pathological processes fundamentally driven by aberrations in the tumor genome Based on this understanding, much progress has been made to develop drugs that improve survival outcomes by targeting the protein products of oncogenes activated by DNA sequence mutation or by gene copy number amplification resulting in higher gene (2021) 2:26 expression levels [10]. Identifying oncogene drivers of LUSC to support development of targeted treatments is urgently needed to improve survival outcomes of these patients.
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