Estudo revela potencial do RKIP para reduzir agressividade do adenocarcinoma pulmonar

O adenocarcinoma pulmonar (LUAD) é o subtipo mais comum de cancro do pulmão de não pequenas células, sendo frequentemente tratado com terapias dirigidas ao recetor do fator de crescimento epidérmico (EGFR). Apesar destes avanços, a resistência aos tratamentos continua a ser um desafio clínico significativo. Neste estudo, a equipa do ICVS investigou o papel da proteína RKIP (Raf Kinase Inhibitory Protein), um supressor de metastização que regula vias de sinalização oncogénicas, na progressão do LUAD e na resposta a terapias anti-EGFR. Utilizando análises in silico, experiências in vitro e modelos in vivo, foi demonstrado que níveis reduzidos de RKIP estão associados a pior sobrevivência neste subtipo de cancro. A sobre-expressão de RKIP diminuiu a migração celular, a integridade de esferoides e o crescimento tumoral, enquanto a sua ausência teve o efeito oposto. Importa destacar que, em modelos animais, a presença de RKIP aumentou a sensibilidade aos inibidores do EGFR, enquanto a sua ausência reduziu a eficácia destes fármacos. Estes resultados sugerem que a RKIP poderá ter potencial como biomarcador no adenocarcinoma pulmonar, contribuindo para otimizar estratégias terapêuticas e ultrapassar a resistência aos tratamentos existentes.

Autores e Afiliações:
Ana Raquel-Cunha^1,2, Joana Pinheiro^1,2, Rui F. Marques^1,2, Patrícia Fontão^1,2, Diana Cardoso-Carneiro^1,2, Adriana Mendes^1,2, Izabela N. F. Gomes³, Ana Carolina Laus³, Renato J. da Silva-Oliveira³, Rui Manuel Reis^1,2,3, Olga Martinho^1,2

¹ Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal;

² ICVS/3Bs-PT Government Associate Laboratory, Braga/Guimarães, Portugal;

³ Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.

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.  

Revista: Molecular Oncology

Link: https://febs.onlinelibrary.wiley.com/doi/10.1002/1878-0261.70096