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

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

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

Kaynakça

1. 1. Sekhoacha M, Riet K, Motloung P, et al. Prostate Cancer Review: Genetics, Diagnosis, Treatment Options, and Alternative Approaches. Molecules. 2022;27(17):5730.
2. 2. Tapper W, Carneiro G, Mikropoulos C, et al. The Application of Radiomics and AI to Molecular Imaging for Prostate Cancer. J Pers Med. 2024;14(3):287.
3. 3. Nouri-Majd S, Salari-Moghaddam A, Aminianfar A, Larijani B, Esmaillzadeh A. Association Between Red and Processed Meat Consumption and Risk of Prostate Cancer: A Systematic Review and Meta-Analysis. Front Nutr. 2022;9:801722.
4. 4. Leung DK, Chiu PK, Ng CF, Teoh JY. Novel Strategies for Treating Castration-Resistant Prostate Cancer. Biomedicines. 2021;9(4):339.
5. 5. Saad F, Hotte SJ. Guidelines for the management of castrate-resistant prostate cancer. Can Urol Assoc J. 2010;4(6):380-384.
6. 6. Kulasegaran T, Oliveira N. Metastatic Castration-Resistant Prostate Cancer: Advances in Treatment and Symptom Management. Curr Treat Options Oncol. 2024;25(7):914-931.
7. 7. Cai M, Song XL, Li XA, et al. Current therapy and drug resistance in metastatic castration-resistant prostate cancer. Drug Resist Updat. 2023;68:100962.
8. 8. Lonergan PE, Tindall DJ. Androgen receptor signaling in prostate cancer development and progression. J Carcinog. 2011;10:20.

9. 9. Pungsrinont T, Kallenbach J, Baniahmad A. Role of PI3K-AKT-mTOR Pathway as a Pro-Survival Signaling and Resistance-Mediating Mechanism to Therapy of Prostate Cancer. Int J Mol Sci. 2021;22(20):11088.
10. 10. Jafarian AH, Mirshekar Nasirabadi K, Etemad S, et al. Molecular Status of BRAF Mutation in Prostate Adenocarcinoma: The Analysis of 100 Cases in North-East of IRAN. Iran J Pathol. 2018;13(4):415-421.
11. 11. Chehrazi-Raffle A, Tukachinsky H, Toye E, et al. Unique Spectrum of Activating BRAF Alterations in Prostate Cancer. Clin Cancer Res. 2023;29(19):3948-3957.
12. 12. Ren G, Liu X, Mao X, et al. Identification of frequent BRAF copy number gain and alterations of RAF genes in Chinese prostate cancer. Genes Chromosomes Cancer. 2012;51(11):1014-1023.
13. 13. Śmiech M, Leszczyński P, Kono H, Wardell C, Taniguchi H. Emerging BRAF Mutations in Cancer Progression and Their Possible Effects on Transcriptional Networks. Genes (Basel). 2020;11(11):1342.
14. 14. Lin K, Baritaki S, Militello L, Malaponte G, Bevelacqua Y, Bonavida B. The Role of B-RAF Mutations in Melanoma and the Induction of EMT via Dysregulation of the NF-κB/Snail/RKIP/PTEN Circuit. Genes Cancer. 2010;1(5):409-420.
15. 15. Blay JY, Cropet C, Mansard S, et al. Long-term activity of vemurafenib in cancers with BRAF mutations: the ACSE basket study for advanced cancers other than BRAFV600-mutated melanoma. ESMO Open. 2023;8(6):102038.
16. 16. Fenor MD, Ruiz-Llorente S, Rodríguez-Moreno JF, et al. MEK inhibitor sensitivity in BRAF fusion-driven prostate cancer. Clin Transl Oncol. 2022;24(12):2432-2440.
17. 17. Al-Salama ZT. Encorafenib: A Review in Metastatic Colorectal Cancer with a BRAF V600E Mutation. Drugs. 2021;81(7):849-856.
18. 18. Tabernero J, Grothey A, Van Cutsem E, et al. Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E-Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study. J Clin Oncol. 2021;39(4):273-284.
19. 19. Dummer R, Flaherty KT, Robert C, et al. COLUMBUS 5-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients with BRAF V600-Mutant Melanoma [published correction appears in J Clin Oncol. 2023;41(12):2301]. J Clin Oncol. 2022;40(36):4178-4188.
20. 20. Pickles OJ, Drozd A, Tee L, Beggs AD, Middleton GW. Paradox breaker BRAF inhibitors have comparable potency and MAPK pathway reactivation to encorafenib in BRAF mutant colorectal cancer. Oncotarget. 2020;11(34):3188-3197.
21. 21. Li Z, Jiang K, Zhu X, et al. Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells. Cancer Lett. 2016;370(2):332-344.
22. 22. Riss TL, Moravec RA, Niles AL, et al. Cell Viability Assays. 2013 May 1 [Updated 2016 Jul 1]. In: Markossian S, Grossman A, Arkin M, et al., editors. Assay Guidance Manual [Internet]. Bethesda (MD): Eli Lilly & Company and the National Center for Advancing Translational Sciences; 2004-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK144065/
23. 23. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature, 2002;417(6892):949–954.
24. 24. Hertzman Johansson C, Egyhazi Brage S. BRAF inhibitors in cancer therapy. Pharmacol Ther. 2014;142(2):176-82.
25. 25. Long GV, Flaherty KT, Stroyakovskiy D, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol. 2017;28(7):1631-1639.
26. 26. Lee YR, Chen M, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat Rev Mol Cell Biol. 2018;19(9):547-562.
27. 27. He Y, Sun MM, Zhang GG. et al. Targeting PI3K/Akt signal transduction for cancer therapy. Sig Transduct Target Ther. 2021;6:425.
28. 28. LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA. Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat. 2008;11(1-2):32-50.
29. 29. Yayan J, Franke KJ, Berger M, Windisch W, Rasche K. Adhesion, metastasis, and inhibition of cancer cells: a comprehensive review. Mol Biol Rep. 2024 Jan 22;51(1):165.
30. 30. Nazarian R, Shi H, Wang Q. et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468:973–977.
31. 31. Kwon WA, Song YS, Lee MK. Strategic Advances in Combination Therapy for Metastatic Castration-Sensitive Prostate Cancer: Current Insights and Future Perspectives. Cancers (Basel). 2024;16(18):3187.
32. 32. Wu P, Gao W, Su M, et al. Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment. Front Cell Dev Biol. 2021;9:641469.