Abstract PR-002: Uncovering novel therapeutic avenues for glioma by exploring the functional interplay of FGFR1, p53, and ribosome biogenesis
Authors: Zisi Asimina , Dratkiewicz Ewelina , Kanellis Dimitris C. , Moussaud Simon , Karlsson Ida , Carén Helena , Bräutigam Lars , Bartek Jiri , Lindström Mikael S. 
Published: March 2024

High-grade gliomas (HGGs) are known for their aggressive nature and resistance to chemotherapy, resulting in a poor prognosis and a pressing need to identify new molecular targets and dependencies. Ribosome biogenesis (RiBi) has emerged as a promising target since many cancer types, including HGGs, rely on high RiBi rates to sustain proliferation. In a previous study, we evaluated the effects of BMH-21, a non-genotoxic small molecule p53 inducer that preferentially blocks RNA pol I transcription, perturbs RiBi, and triggers nucleolar stress (Zisi A et al., Neuro Oncol, 2023). We tested BMH-21 in adult and pediatric HGG cell lines and a zebrafish transplant model. Treatment with BMH-21 reduced glioma cell viability, activated cell death programs, and impaired growth of transplanted HGG cells in zebrafish. A chemical synergy screen with BMH-21 revealed synergistic effects among inhibitors of the Fibroblast Growth Factor Receptor (FGFR) pathway, such as Erdafitinib, suggesting its involvement in the cellular responses triggered by BMH-21. Indeed, FGF2 showed nucleolar localization that was altered by BMH-21, which also induced FGF2 expression, secretion, and FGFR1 activation with downstream effects on the SOX2 levels (Zisi A et al., Neuro Oncol, 2023). These effects were consistently observed using other RNA pol I inhibitors or siRNA-based genetic depletion of POLR1A, underlining a mechanistic interplay that remains to be elucidated. FGFR1 is amplified or mutated in various pediatric brain tumors, thus a candidate for targeted therapies. We noted that BMH-21 while activating the FGFR1 pathway, eventually suppressed FGFR1 protein levels, but this was not consistently seen in all cell lines tested, a finding we here investigated further, being a potentially important aspect of FGFR1 targeting. Our new data show that following BMH-21 treatment, FGFR1 protein was markedly downregulated in wild-type p53 glioma lines. Other non-genotoxic p53-activating small molecules such as Curaxin CBL0137 and Nutlin-3a also markedly reduced FGFR1. siRNA-based p53 depletion prevented FGFR1 protein suppression in response to BMH-21 or Nutlin-3a. While Erdafitinib had modest growth inhibitory effects as monotherapy, its combination with Nutlin-3a displayed potent anti-proliferative effects in wt p53 glioma cell lines. In summary, FGFR1 emerges as a target of p53-dependent repression in glioma cells, analogous to the repressive effects that p53 has on other amplified oncogenes. Our data supports the design of FGFRi-based combination therapies with non-genotoxic p53 inducers and RiBi inhibitors while considering p53 status, and clearly warrants further testing against HGG.

Citation Format: Asimina Zisi, Ewelina Dratkiewicz, Dimitris C. Kanellis, Simon Moussaud, Ida Karlsson, Helena Carén, Lars Bräutigam, Jiri Bartek, Mikael S. Lindström. Uncovering novel therapeutic avenues for glioma by exploring the functional interplay of FGFR1, p53, and ribosome biogenesis [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr PR-002.