RNase1-driven ALK-activation is an oncogenic driver and therapeutic target in non-small cell lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Targeted therapies are effective for non-small cell lung cancer (NSCLC) with specific mutations (EGFR, KRAS, ALK).
• A significant subset of NSCLC patients (~35-50%) lack these mutations and do not benefit from current targeted treatments.
• Novel therapeutic strategies are needed for this non-mutated NSCLC population.

Purpose of the Study:

• To investigate a non-canonical role of human secretory ribonuclease 1 (RNase1) in lung cancer.
• To identify RNase1 as a potential therapeutic target for non-mutated NSCLC.
• To evaluate the efficacy of ALK inhibitors in RNase1-driven ALK-activation (RDAA) positive NSCLC.

Main Methods:

• Investigated RNase1's interaction with wild-type ALK in lung cancer cells.
• Assessed the oncogenic potential of RNase1-driven ALK-activation (RDAA) in vitro and in vivo models.
• Utilized immunohistochemical staining on NSCLC tissue cohorts to identify RDAA-positive patients.
• Evaluated the response of RDAA-positive NSCLC xenografts to FDA-approved ALK inhibitors.

Main Results:

• RNase1 binds and activates wild-type ALK, leading to RNase1-driven ALK-activation (RDAA).
• RDAA enhances cancer cell proliferation, migration, colony formation, and tumor growth in vivo.
• RDAA-positive NSCLC cells are sensitive to ALK inhibitors, with significant tumor growth suppression and improved survival observed in xenograft models.
• RDAA was identified in 8.5-10.4% of NSCLC patients, with notable objective responses (including complete response) in RDAA-positive patients treated with ALK inhibitors.

Conclusions:

• RNase1 acts as an oncogenic driver through RNase1-driven ALK-activation (RDAA) in a subset of NSCLC.
• RDAA represents a novel therapeutic target for non-mutated NSCLC.
• Targeted therapy with ALK inhibitors is a viable and effective strategy for RDAA-positive NSCLC patients.