Journal Article

Unveiling the signaling network of FLT3-ITD AML improves drug sensitivity prediction

Minnella, Gessica, Marra, John Donald, Venafra, Veronica, Perfetto, Livia, Graziosi, Simone, Pepe, Gerardo, Massacci, Giorgia, Helmer Citterich, Manuela, Sacco, Francesca, Frioni, Filippo, Chiusolo, Patrizia, Pugliese, Giusj Monia, Iannuccelli, Marta, Böttcher, Martin, Latini, Sara, Mougiakakos, Dimitros, Fischer, Thomas, Bica, Valeria

2024

Overview

Currently, the identification of patient-specific therapies in cancer is mainly informed by personalized genomic analysis. In the setting of acute myeloid leukemia (AML), patient-drug treatment matching fails in a subset of patients harboring atypical internal tandem duplications (ITDs) in the tyrosine kinase domain of the FLT3 gene. To address this unmet medical need, here we develop a systems-based strategy that integrates multiparametric analysis of crucial signaling pathways, and patient-specific genomic and transcriptomic data with a prior knowledge signaling network using a Boolean-based formalism. By this approach, we derive personalized predictive models describing the signaling landscape of AML FLT3-ITD positive cell lines and patients. These models enable us to derive mechanistic insight into drug resistance mechanisms and suggest novel opportunities for combinatorial treatments. Interestingly, our analysis reveals that the JNK kinase pathway plays a crucial role in the tyrosine kinase inhibitor response of FLT3-ITD cells through cell cycle regulation. Finally, our work shows that patient-specific logic models have the potential to inform precision medicine approaches.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Acute myeloid leukemia / Analysis / Apoptosis / Boolean / Boolean model / Cancer Biology / Cancer therapies / cancer therapy / Care and treatment / Cell cycle / Cell Line / Computational and Systems Biology / Datasets / Drug Resistance / FLT3 gene / fms-Like Tyrosine Kinase 3 - genetics / Genomic analysis / Genotype & phenotype / Health aspects / Humans / Integrated approach / Kinases / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - genetics / Logic / MAP Kinase Signaling System / Medical prognosis / mouse / Patients / Precision medicine / Prediction models / Proteins / Signal Transduction / Transcriptomics / Tyrosine / tyrosine kinase