Christian DeLemos

Background: Prostate cancer (PCa) is one of the most common forms of cancer among with about 1,276,106 new cases and 358,989 deaths in 2018 worldwide.¹ PCa primarily affects middle aged men between 45-60.¹ PCa is classified in 4 stages (I-IV).¹ Life expectancy in early stages (I-II) is 99% for >10 years while life expectancy in late stages (III-IV) is 30% for 5 years.² Metastatic PCa progresses to castration-resistant PCa (CRPC), rendering it unresponsive to androgen deprivation therapy (ADT). This transition is a primary cause of morbidity and mortality in PCa patients and is an end-stage where effective treatment options are limited.² Fibroblast Growth Factor 1 (FGFR1) expression is found to drive PCa progression and increased in CRPC bone metastases compared to primary untreated disease, suggesting a potential role in disease advancement and therapy resistance.^3,4,5 FGFR1 is implicated in various cellular processes, including cell proliferation, migration, and angiogenesis, all of which contribute to tumor growth and metastasis.⁶

Objective: This outline explores the therapeutic potential of targeting FGFR1 in CRPC by elucidating its upregulation mechanisms, downstream effects, and the clinical relevance of FGFR1 inhibitors like pemigatinib.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2024 using the following keywords: “Prostate Cancer”, “FGFR1”, “Castration-Resistant Prostate Cancer”, “Prostate Neoplasms”.

Results: CircFGFR1int2 facilitates FGFR1 transcription by recruiting transcription activators P65/FUS and interacting with the FGFR1 promoter.⁵ CircFGFR1int2 counteracts the inhibitory effects of miR-4687-5p on FGFR1 mRNA post-transcriptionally, thereby enhancing FGFR1 expression and reinforcing its oncogenic effects in PCa.⁵ Fibroblast Growth Factor 1 (FGF1) treatment activates the downstream NF-κB pathway specifically in DU145 cells (high FGFR1 expression), suggesting cross-talk between FGFR1 signaling and NF-κB pathway in PCa cells.³ NF-kB leads to inflammation, which facilitates the advancement of cancer.³ Activation of FGFR1 in prostate cells leads to increased expression of COX-2 and infiltration of macrophages, indicative of inflammation in TRAMP mice and JOCK1 mice.³ Additionally, there are 2 FGFR1 isoforms (α/β) associated with different genes and pathways in PCa.⁴ Intracardiac injection of PCa cells overexpressing FGFR1α or FGFR1β leads to increased bone metastases and reduced survival in mice.⁴ FGFR1 induces the expression of Ladinin 1 (LAD1), which is associated with cellular movement and implicated in cancer progression.⁴ Silencing of LAD1 in FGFR1β-overexpressing PCa cells reduces bone metastases and improves survival in mice.⁴ For potential treatments, Pemigatinib, inhibitor of FGFR1-3, led to a reduction in pathological area of CRPC to 22.4 ± 2.1%. Combination regimen (enzalutamide plus pemigatinib) significantly blocked tumor progression and resulted in very rare or no pathological areas to 15.2 ± 3.9% by the end of the experiment. ⁶

Conclusion: Through mechanisms involving upregulation of FGFR1 expression such as circFGFR1int2, downstream FGFR1 signaling involving NF-kB and LAD1, and subsequent inflammation, FGFR1 has emerged as a central player in the molecular landscape of advanced PCa. Clinical translation of these preclinical findings is exemplified by Pemigatinib, offering new avenues for personalized therapy and combination strategies in CRPC management.

Works Cited:

1. Sekhoacha M, Riet K, Motloung P, Gumenku L, Adegoke A, Mashele S. Prostate Cancer Review: Genetics, Diagnosis, Treatment Options, and Alternative Approaches. Molecules. 2022;27(17):5730. Published 2022 Sep 5. doi:10.3390/molecules27175730
2. Wasim S, Lee SY, Kim J. Complexities of Prostate Cancer. Int J Mol Sci. 2022;23(22):14257. Published 2022 Nov 17. doi:10.3390/ijms232214257
3. Wang C, Ke Y, Liu S, et al. Ectopic fibroblast growth factor receptor 1 promotes inflammation by promoting nuclear factor-κB signaling in prostate cancer cells. J Biol Chem. 2018;293(38):14839-14849. doi:10.1074/jbc.RA118.002907
4. Labanca E, Yang J, Shepherd PDA, et al. Fibroblast Growth Factor Receptor 1 Drives the Metastatic Progression of Prostate Cancer. Eur Urol Oncol. 2022;5(2):164-175. doi:10.1016/j.euo.2021.10.001
5. Wang R, Zhong J, Pan X, et al. A novel intronic circular RNA circFGFR1^int2up-regulates FGFR1 by recruiting transcriptional activators P65/FUS and suppressing miR-4687-5p to promote prostate cancer progression. J Transl Med. 2023;21(1):840. Published 2023 Nov 22. doi:10.1186/s12967-023-04718-y
6. Chiodelli P, Coltrini D, Turati M, et al. FGFR blockade by pemigatinib treats naïve and castration resistant prostate cancer. Cancer Lett. 2022;526:217-224. doi:10.1016/j.canlet.2021.11.030