Neurokinin-1 receptor promotes non-small cell lung cancer progression through transactivation of EGFR

Area of Science:

• Oncology
• Molecular Biology
• G protein-coupled receptor signaling

Background:

• Lung cancer remains a leading cause of cancer mortality globally.
• The role of G protein-coupled receptor neurokinin-1 (NK1R) in lung cancer pathogenesis is not well understood.
• Target therapies have advanced, but improved treatments are still needed.

Purpose of the Study:

• To investigate the role of NK1R in lung cancer.
• To explore the relationship between NK1R and epidermal growth factor receptor (EGFR) signaling in lung cancer.
• To evaluate NK1R as a potential therapeutic target for lung cancer.

Main Methods:

• Analysis of NK1R expression in human lung cancer tissues and transcriptomes.
• Investigation of NK1R and EGFR co-expression and co-localization.
• In vitro studies using NK1R antagonist aprepitant and NK1R knockdown.
• In vivo tumor growth studies in nude mice.
• Assessment of lung cancer cell sensitivity to EGFR inhibitors in combination with NK1R antagonist.

Main Results:

• NK1R is significantly upregulated in lung cancer and associated with advanced stages and poor prognosis.
• NK1R co-expresses and interacts with EGFR, leading to EGFR transactivation and downstream signaling (ERK1/2, Akt).
• NK1R activation promotes lung cancer cell proliferation, EMT, migration, and MMP2/14 expression.
• Aprepitant inhibits NK1R, repressing proliferation and migration, and slowing tumor growth in vivo.
• NK1R inhibition increases lung cancer cell sensitivity to gefitinib and osimertinib.

Conclusions:

• NK1R plays a critical role in lung cancer development, partly through crosstalk with EGFR signaling.
• Targeting the NK1R-EGFR axis presents a promising therapeutic strategy for lung cancer.
• NK1R inhibition may overcome resistance to existing EGFR-targeted therapies.