Network Analysis Reveals Synergistic Genetic Dependencies for Rational Combination Therapy in Philadelphia Chromosome–Like Acute Lymphoblastic Leukemia
Open Access
- 1 July 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 27 (18), 5109-5122
- https://doi.org/10.1158/1078-0432.ccr-21-0553
Abstract
Purpose: Systems biology approaches can identify critical targets in complex cancer signaling networks to inform new therapy combinations that may overcome conventional treatment resistance. Experimental Design: We performed integrated analysis of 1,046 childhood B-ALL cases and developed a data-driven network controllability-based approach to identify synergistic key regulator targets in Philadelphia chromosome-like B-acute lymphoblastic leukemia (Ph-like B-ALL), a common high-risk leukemia subtype associated with hyperactive signal transduction and chemoresistance. Results: We identified 14 dysregulated network nodes in Ph-like ALL involved in aberrant JAK/STAT, Ras/MAPK, and apoptosis pathways and other critical processes. Genetic co-targeting of the synergistic key regulator pair STAT5B and BCL2-associated athanogene 1 (BAG1) significantly reduced leukemia cell viability in vitro. Pharmacologic inhibition with dual small molecule inhibitor therapy targeting this pair of key nodes further demonstrated enhanced anti-leukemia efficacy of combining the BCL-2 inhibitor venetoclax with the tyrosine kinase inhibitors ruxolitinib or dasatinib in vitro in human Ph-like ALL cell lines and in vivo in multiple childhood Ph-like ALL patient-derived xenograft models. Consistent with network controllability theory, co-inhibitor treatment also shifted the transcriptomic state of Ph-like ALL cells to become less like kinase-activated BCR-ABL1-rearranged (Ph+) B-ALL and more similar to prognostically-favorable childhood B-ALL subtypes. Conclusions: Our study represents a powerful conceptual framework for combinatorial drug discovery based on systematic interrogation of synergistic vulnerability pathways with pharmacologic inhibitor validation in preclinical human leukemia models.Keywords
Funding Information
- NIH
- National Child Health and Human Development (T32HD043021)
- NIH
- NCI (K12CA076931)
- University of Pennsylvania (K08CA184418)
- Department of Defense Translational Team Science
- Canadian Institutes of Health Research Doctoral Foreign Study (433117)
This publication has 51 references indexed in Scilit:
- Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibitionThe Journal of Experimental Medicine, 2012
- BAG1: The Guardian of Anti-Apoptotic Proteins in Acute Myeloid LeukemiaPLOS ONE, 2011
- Therapeutic target database update 2012: a resource for facilitating target-oriented drug discoveryNucleic Acids Research, 2011
- ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapyLeukemia, 2011
- Controllability of complex networksNature, 2011
- Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcomeBlood, 2010
- Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1Nature, 2009
- Systematic and integrative analysis of large gene lists using DAVID bioinformatics resourcesNature Protocols, 2008
- PID: the Pathway Interaction DatabaseNucleic Acids Research, 2008
- Mcl-1: a highly regulated cell death and survival controllerJournal of Biomedical Science, 2006