Abstract 18P
Background
Turbine’s Simulated Cell™ platform models cancer cell signaling to predict cell viability and to identify new drug targets. By simulating perturbations of the DNA-damage response (DDR) pathway, we identified NEK1 as a novel dependency. NEK1 is part of the NIMA-related kinase family, involved in DDR, cell cycle, and mitosis making it an interesting candidate for antitumor intervention.
Methods
We performed an in silico drug modifier-like screen for PARP inhibitors with the Simulated Cell™. To confirm predictions, we performed gene CRISPR knock-out (KO) in cancer cell lines and measured cell growth and viability. To validate the role of candidate genes in vivo, we performed CRISPR-KO in cell derived xenografts (CDX); the tumors were extracted for RNA sequencing. To assess in silico predicted sensitizing mechanisms we performed an in vitro CRISPR KO screen on 7700 genes in combination with target gene KO.
Results
Our platform predicted NEK1 KO to sensitize cancer cells to PARP inhibition; we further predicted a set of cancer cell lines to be sensitive or resistant to NEK1 KO alone. We confirmed that medulloblastoma (DAOY) and head and neck carcinoma (HSC-2) cells were dependent on NEK1 activity for proliferation in vitro, while the negative control (predicted to be resistant in silico) breast cancer cells (HCC1806) were not. The CDX model of both sensitive cell lines showed a reduction in tumor growth upon NEK1 KO. RNA-seq analysis revealed that NEK1 KO leads to increased JAK-STAT activation and altered cytokine production in vivo. The pathway enrichment analysis of the CRISPR KO screen suggests co-targeting inflammation- and immune response- related genes sensitized cancer cells to NEK1 KO.
Conclusions
Turbine’s Simulated Cell™ platform predicted NEK1 dependency in cell lines in which the DepMap dataset suggested otherwise. We confirmed our prediction of reduced cellular proliferation in vitro and reduced tumor growth in vivo. Additionally, we revealed that NEK1 effects on tumor growth might be mediated by changes in immune regulation, and that co-targeting pathways involved in this process may increase the efficacy of NEK1 inhibition. These data validate Turbine’s platform as a target identification solution and suggest that NEK1 is a promising anticancer target.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Turbine Simulated Cell Technologies Ltd.
Funding
Turbine Simulated Cell Technologies Ltd.
Disclosure
M.V. Ruiz-Pérez, I. Gaspar, I. Fekete, C. Szántai-Kis, S. Connolly, B. Elek, M. Djurec, C. Hegedüs, I. Taisz: Financial Interests, Institutional, Full or part-time Employment, Employee: Turbine Ltd. D. Veres: Financial Interests, Institutional, Ownership Interest: Turbine Ltd.