Abstract 1632: Dissecting AMBRA1-cyclin D axis deregulation in embryonal tumors of the central nervous system

Abstract Dissecting AMBRA1-cyclin D axis deregulation in embryonal tumors of the centralnervous systemEmbryonal tumors of the central nervous system (CNS) are malignant growths originating from embryonic neural stem cells, primarily affecting pediatric patients. These tumors pose a significant threat to children's health, leading to high morbidity and mortality rates. To improve survival rates and reduce morbidity, there is a critical need for advanced molecular diagnostics and innovative therapies. Among these tumors are medulloblastomas (MB) and other embryonal tumors, previously classified as primitive neuroectodermal tumors (CNS-PNET). These malignancies are characterized by uncontrolled cell proliferation, primarily driven by abnormalities in cell cycle proteins. Consequently, targeting cell cycle regulators has emerged as a promising approach for their treatment. Two key signaling pathways, namely the MYC and the cyclin D-CDK-RB pathway, govern the decision-making process related to genome replication. Mutations in both MYC and the CDK4/6/cyclin D pathway, leading to the functional inactivation of RB, have been identified as relevant factors in the development of CNS-PNET and medulloblastomas. Our seminal research has highlighted the crucial role of AMBRA1, an upstream master regulator orchestrating the transition from G1 to S phase (Maiani & Milletti et al., 2021). Specifically, AMBRA1 modulates the abundance of D-type cyclins and MYC by facilitating their proteasomal degradation, thereby ensuring genomic stability during DNA replication.Based on these discoveries, we propose that AMBRA1 functions as a multifaceted tumor suppressor across various cancer types. An unbiased Sleeping Beauty analysis identified AMBRA1 as a genetic driver of CNS-PNET, providing a strong foundation for investigating its role further (Beckmann et al., 2019). We hypothesize that the simultaneous deletion of AMBRA1 and p53 in an inducible knockout mouse model can lead to the spontaneous development of CNS-PNET or medulloblastoma, contingent on the specific targeted cell lineage. Additionally, our research demonstrates that AMBRA1 deficiency confers resistance to CDK4/6 inhibitors while creating a synthetic lethality with CHK1 inhibitors. Consequently, we propose that a comparative analysis of AMBRA1, D-type cyclins, and Myc family expression levels could serve as a diagnostic marker. This marker could facilitate patient-based stratification for CHK1 inhibitor treatment efficacy, enabling the differentiation of non- responsive cases to CDK4/6 chemotherapy. Citation Format: Giacomo Milletti, Giulia Cadeddu, Alba Adelantado Rubio, Caterina Ferraina, Apolinar Maya-Mendoza, Francesco Cecconi. Dissecting AMBRA1-cyclin D axis deregulation in embryonal tumors of the central nervous system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1632.