Piotrowska Anna, Nowak Joanna I, Wierzbicka Justyna M, Domżalski Paweł, Górska-Arcisz Monika, Sądej Rafał, Popiel Delfina, Wieczorek Maciej, Żmijewski Michał A
Faculty of Medicine, Department of Histology, Medical University of Gdańsk, Dębinki 1a, 80-384 Gdańsk, Poland.
Laboratory of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, Dębinki 1, 80-384 Gdańsk, Poland.
Int J Mol Sci. 2024 Feb 21;25(5):2505. doi: 10.3390/ijms25052505.
Regardless of the unprecedented progress in malignant melanoma treatment strategies and clinical outcomes of patients during the last twelve years, this skin cancer remains the most lethal one. We have previously documented that vitamin D and its low-calcaemic analogues enhance the anticancer activity of drugs including a classic chemotherapeutic-dacarbazine-and an antiangiogenic VEGFRs inhibitor-cediranib. In this study, we explored the response of A375 and RPMI7951 melanoma lines to CPL304110 (CPL110), a novel selective inhibitor of fibroblast growth factor receptors (FGFRs), and compared its efficacy with that of AZD4547, the first-generation FGFRs selective inhibitor. We also tested whether 1,25(OH)D, the active form of vitamin D, modulates the response of the cells to these drugs. CPL304110 efficiently decreased the viability of melanoma cells in both A375 and RPMI7951 cell lines, with the IC50 value below 1 µM. However, the metastatic RPMI7951 melanoma cells were less sensitive to the tested drug than A375 cells, isolated from primary tumour site. Both tested FGFR inhibitors triggered G0/G1 cell cycle arrest in A375 melanoma cells and increased apoptotic/necrotic SubG1 fraction in RPMI7951 melanoma cells. 1,25(OH)D modulated the efficacy of CPL304110, by decreasing the IC50 value by more than 4-fold in A375 cell line, but not in RPMI7951 cells. Further analysis revealed that both inhibitors impact vitamin D signalling to some extent, and this effect is cell line-specific. On the other hand, 1,25(OH)D, have an impact on the expression of FGFR receptors and phosphorylation (FGFR-Tyr653/654). Interestingly, 1,25(OH)D and CPL304110 co-treatment resulted in activation of the ERK1/2 pathway in A375 cells. Our results strongly suggested possible crosstalk between vitamin D-activated pathways and activity of FGFR inhibitors, which should be considered in further clinical studies.
尽管在过去十二年中恶性黑色素瘤的治疗策略和患者临床疗效取得了前所未有的进展，但这种皮肤癌仍然是最致命的。我们之前已证明维生素D及其低钙类似物可增强包括经典化疗药物达卡巴嗪和抗血管生成VEGFRs抑制剂西地尼布在内的药物的抗癌活性。在本研究中，我们探究了A375和RPMI7951黑色素瘤细胞系对新型成纤维细胞生长因子受体（FGFRs）选择性抑制剂CPL304110（CPL110）的反应，并将其疗效与第一代FGFRs选择性抑制剂AZD4547进行比较。我们还测试了维生素D的活性形式1,25(OH)D是否调节细胞对这些药物的反应。CPL304110有效降低了A375和RPMI7951细胞系中黑色素瘤细胞的活力，IC50值低于1μM。然而，与从原发性肿瘤部位分离的A375细胞相比，转移性RPMI7951黑色素瘤细胞对受试药物的敏感性较低。两种受试FGFR抑制剂均在A375黑色素瘤细胞中引发G0/G1细胞周期阻滞，并增加RPMI7951黑色素瘤细胞中凋亡/坏死的亚G1期比例。1,25(OH)D通过将A375细胞系中的IC50值降低4倍以上来调节CPL304110的疗效，但在RPMI7951细胞中则不然。进一步分析表明，两种抑制剂在一定程度上影响维生素D信号传导，且这种作用具有细胞系特异性。另一方面，1,25(OH)D对FGFR受体的表达和磷酸化（FGFR-Tyr653/654）有影响。有趣的是，1,25(OH)D与CPL304110联合处理导致A375细胞中ERK1/2通路的激活。我们的结果强烈表明维生素D激活的通路与FGFR抑制剂的活性之间可能存在相互作用，这在进一步的临床研究中应予以考虑。
