# RKIP overexpression reduces lung adenocarcinoma aggressiveness and sensitizes cells to EGFR‐targeted therapies

## TL;DR

RKIP overexpression reduces lung adenocarcinoma aggressiveness and improves response to EGFR-targeted therapies, suggesting its potential as a therapeutic modulator.

## Contribution

The study reveals RKIP's role in modulating LUAD progression and EGFR therapy response through key oncogenic pathways.

## Key findings

- RKIP overexpression reduces tumor migration, spheroid integrity, and growth in LUAD.
- Low RKIP expression correlates with poorer survival outcomes in LUAD patients.
- RKIP overexpression enhances sensitivity to anti-EGFR treatments, while its loss promotes resistance.

## Abstract

Lung adenocarcinoma (LUAD), the most common subtype of non‐small‐cell lung cancer (NSCLC), is often driven by mutations, particularly in epidermal growth factor receptor (EGFR), that guide targeted therapy choices. However, resistance to these treatments remains a major clinical challenge. Raf kinase inhibitory protein (RKIP), encoded by the PEBP1 gene, a metastasis suppressor, modulates key oncogenic pathways and may influence tumor aggressiveness and therapy response. Yet, its specific role in NSCLC remains unclear. This study investigates the influence of RKIP expression on NSCLC aggressiveness and explores its impact on therapy response, particularly to EGFR‐targeted therapies. In silico analyses revealed that lower RKIP mRNA expression correlates with poorer survival outcomes in LUAD patients but not in other NSCLC subtypes. Genetic modulation of RKIP expression in LUAD cell lines demonstrated that its overexpression reduced migration, spheroid integrity, and suppressed tumor growth, whereas RKIP knockout had opposite effects, particularly in vivo. Expression profiling showed that RKIP overexpression impacts the activation of mitogen‐activated protein kinase (MAPK), RAC serine/threonine‐protein kinase (AKT), and signal transducer and activator of transcription 3 (STAT3) pathways, as well as processes related to extracellular matrix regulation and inflammatory responses. Importantly, in vitro and in vivo experiments demonstrated that RKIP overexpression sensitizes cells to anti‐EGFR treatments, whereas RKIP knockout diminished their sensitivity. Overall, our findings indicate that RKIP modulates LUAD progression and response to EGFR‐targeted therapies, although its clinical value as a biomarker requires further validation. These findings highlight RKIP's potential in overcoming therapeutic resistance and the need for further investigation into its regulatory mechanisms.

RKIP, a metastasis suppressor protein, modulates key oncogenic pathways in lung adenocarcinoma. In silico analyses linked low RKIP expression to poor survival. Functional studies revealed RKIP overexpression reduces tumor aggressiveness and enhances sensitivity to EGFR‐targeted therapies, while its loss promotes resistance. RKIP expression has an impact on MAPK, AKT, and STAT3 signaling, supporting its potential as a biomarker and therapeutic modulator.