EGFR e STAT3 como alvos terapêuticos em carcinoma da próstata ETV1-positivo

Investigadores do Grupo de Oncogenética do IPO Porto, em colaboração com o Instituto de Ciências Biomédicas Abel Salazar da Univerisdade do Porto (ICBAS), identificaram uma via de sinalização que impulsiona a agressividade de carcinomas da próstata com sobre-expressão de ETV1. A equipa de investigação descobriu que a activação das vias EGFR e STAT3 promove o comportamento maligno destes carcinomas. A co-inibição destas vias de sinalização com Erlotinib (inibidor de EGFR) e TTI-101 (inibidor de STAT3), suprimiu de forma sinérgica o crescimento tumoral em modelos celulares 2D e 3D de próstata com sobre-expressão de ETV1. Estes resultados apontam para uma estratégia terapêutica promissora dirigida aos 8–10% dos carcinomas da próstata caracterizados por ETV1—um subgrupo agressivo, associado a pior prognóstico, e que atualmente carece de opções terapêuticas de precisão eficazes.

Autores e Afiliações:

Elsa Gomes Paiva^1,2, Bernardo Orr¹, Ana Azeredo^1,3, Andreia Brandão¹, Manuel R Teixeira^1,4,5, Paula Paulo^1,5*

¹ Cancer Genetics Group, IPO Porto Research Center (CI‐IPOP)/RISE@CI‐IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center, Portugal

² PhD Program in Biomedical Sciences, School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Portugal

³ Master Program in Oncology, School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Portugal

⁴ Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC Raquel Seruca), Portugal

⁵ School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Portugal

*Correspondence to P. Paulo, Portuguese Oncology Institute of Porto (IPO Porto), 4200‐072 Porto, Portugal, Tel: +351225084000, ext. 5609, E‐mail: [email protected]

Abstract:

Prostate cancer (PCa) is the fifth leading cause of cancer‐related death. The lack of data linking genomic alterations to targeted treatment strategies has hindered progress in disease management. Genomic rearrangements involving the ETS transcription factors ERG or ETV1 are among the most frequent genetic alterations in PCa; however, their clinical utility remains elusive. Using PCa cells overexpressing ETV1 or ERG, representing early and advanced disease stages, we unveiled a positive feedback loop between ETV1 and EGFR, with STAT3 acting as a downstream effector of ETV1–EGFR signaling. Analysis of external datasets revealed that both EGFR and STAT3 are significantly upregulated in ETV1‐positive PCa, consistent with ChIP‐seq data identifying them as direct ETV1 targets. Accordingly, combined inhibition of EGFR and STAT3 using Erlotinib and TTI‐101, respectively, led to a significant reduction in 2D and 3D cell growth of early and advanced PCa cells overexpressing ETV1. Collectively, our findings highlight EGFR–STAT3 activation as a novel ETV1‐regulated oncogenic pathway, providing a rationale for repurposing EGFR inhibitors in combination with STAT3 inhibitors as a therapeutic strategy for the 8–10% of prostate carcinomas characterized by ETV1 rearrangements/overexpression.

Revista: Molecular Oncology

Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC12591323/#mol270069-sec-0025