Faculty, Staff and Student Publications

Publication Date

4-18-2025

Journal

Signal Transduction and Targeted Therapy

Abstract

Targeted therapy has achieved significant success in the treatment of non-small cell lung cancer (NSCLC), particularly in patients harboring common oncogenic driver mutations such as EGFR, KRAS, and ALK rearrangement. However, ~35-50% of NSCLC patients without tyrosine kinase mutation or rearrangement (non-mutated) cannot benefit from these targeted treatments, highlighting the urgent need for novel therapeutic strategies for this patient population. In this study, we report a non-canonical role of human secretory ribonuclease 1 (RNase1), which binds to and activates wild-type ALK in lung cancer cells, thereby triggering its downstream signaling pathway. RNase1-driven ALK-activation (RDAA) cells exhibit enhanced cell proliferation, migration, and colony formation. Additionally, RDAA facilitates tumor formation in fibroblast models, further underscoring its oncogenic potential in vivo. Importantly, RDAA lung cancer cells exhibit marked sensitivity to FDA-approved ALK inhibitors. Tumor growth suppression and survival were substantially improved in both RDAA-positive NSCLC cell line-derived and patient-derived xenograft tumor models treated with ALK inhibitors. Monoclonal antibodies against RNase1 and phosphorylated-ALK were used to analyze two different human NSCLC tissue cohorts by immunohistochemical staining identified 10.4% (5/48) and 8.5% (100/1173) patients who were RDAA positive, respectively. Notably, among the nine RDAA-positive NSCLC patients who accepted ALK inhibitor treatment, five achieved objective response including two who experienced complete response (CR). Together, the current study identifies RDAA as an oncogenic driver and proposes an effective targeted therapy strategy for non-mutated NSCLC patients.

Keywords

Humans, Carcinoma, Non-Small-Cell Lung, Anaplastic Lymphoma Kinase, Mice, Animals, Lung Neoplasms, Ribonuclease, Pancreatic, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Signal Transduction, Female, Carrier Proteins

DOI

10.1038/s41392-025-02206-x

PMID

40246819

PMCID

PMC12006399

PubMedCentral® Posted Date

4-18-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

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