Cytotoxic and Apoptotic Agent Encorafenib Controversially Alters Invasive Properties of Castration-Resistant Prostate Cancer Cells with High and Moderate Metastatic Potential

Yıl 2025, Cilt: 47 Sayı: 2, 263 - 270, 27.02.2025

Işıl Ezgi Eryılmaz , Ceyda Colakoglu Bergel , Bilge Arıöz , Ünal Egeli

Öz

Metastatic castration-resistant prostate cancer (mCRPC) is a highly aggressive form of prostate cancer (PCa) with limited treatment options and poor prognosis. BRAF mutations, although rare, contribute to the progression of PCa by activating the MAPK signaling pathway, which is implicated in cellular proliferation, survival, and metastasis. In this study, we first investigated the potential anticancer and anti-invasive effects of Encorafenib (Enco), a second-generation BRAF inhibitor, in mCRPC cell lines with varying metastatic potentials: moderate metastatic DU145 (BRAF-mutated) and high metastatic PC3 (PTEN-null). Our results showed that Enco reduced cell viability and induced apoptosis in both cell lines in a concentration- and time-dependent manner, with DU145 cells being more sensitive. While Enco inhibited migration in PC3 cells, it had no significant effect on the migration of DU145 cells. Furthermore, Enco treatment increased the expression of genes related to angiogenesis and invasion (VEGF-a, HIF1-a, MMP9, and MMP2) in both cell lines. These findings suggest that while Enco may have potential as a cytotoxic agent for mCRPC, its effects on migration, invasion, and gene expression may vary based on the specific genetic alterations of the cancer cells. This highlights the need for personalized treatment strategies and the potential for adaptive resistance mechanisms. Further studies, particularly combination therapies targeting multiple signaling pathways, are necessary to improve the therapeutic efficacy of Enco in mCRPC.

Anahtar Kelimeler

Metastatic castration-resistant prostate cancer, Encorafenib, BRAF, PTEN, migration, invasion

Sitotoksik ve Apoptotik Ajan Encorafenib, Yüksek ve Orta Derecede Metastatik Potansiyele Sahip Kastrasyona Dirençli Prostat Kanseri Hücrelerinin İnvaziv Özelliklerini Tartışmalı Şekilde Değiştirir

Öz

Metastatik kastrasyona-dirençli prostat kanseri (mKDPK), sınırlı tedavi seçeneği ve kötü prognozu olan oldukça agresif bir prostat kanseri (PKa) formudur. BRAF mutasyonları, nadir olmalarına rağmen, hücresel proliferasyon, hayatta kalma ve metastazda rol oynayan MAPK sinyal yolunu aktive ederek PKa'nın ilerlemesine katkıda bulunmaktadır. Bu çalışmada, farklı metastatik potansiyellere sahip mKDPK hücre hatlarında, ikinci nesil BRAF inhibitörü olan Encorafenib (Enco)'nin potansiyel antikanser ve anti-invaziv etkilerini orta düzeyde metastatik DU145 (BRAF-mutasyona uğramış) ve yüksek metastatik PC3 (PTEN-null) mKDPK hücre hatlarında ilk kez araştırdık. Sonuçlarımız, Enco'nun her iki hücre hattında da konsantrasyona ve zamana bağlı olarak hücre canlılığını azalttığını ve apoptozu indüklediğini göstermiş ve DU145 hücreleri ilaca daha duyarlı bulunmuştur. Enco, PC3 hücrelerinde migrasyonu inhibe ederken, DU145 hücrelerinde migrasyon üzerinde anlamlı bir etki göstermemiştir. Ayrıca, Enco tedavisi her iki hücre hattında da angiogenez ve invazyonla ilişkili genlerin (VEGF-a, HIF1-a, MMP9 ve MMP2) ekspresyonunu arttırmıştır. Bu bulgular, Enco'nun mKDPK için sitotoksik bir ajan olarak potansiyel olabileceğini, ancak migrasyon, invazyon ve gen ekspresyonu üzerindeki etkilerinin kanser hücrelerinin spesifik genetik değişikliklerine bağlı olarak değişebileceğini düşündürmektedir. Bu durum, kişiselleştirilmiş tedavi stratejilerinin önemini ve adaptif direnç mekanizmalarının potansiyelini vurgulamaktadır. Enco'nun mKDPK'deki terapötik etkinliğini artırmak için özellikle birden fazla sinyal yolunu hedefleyen kombinasyon tedavilerine yönelik daha fazla çalışmaya ihtiyaç vardır.

Anahtar Kelimeler

Metastatik kastrasyona-dirençli prostat kanseri, Encorafenib, BRAF, PTEN, migrasyon, invazyon

Kaynakça

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