Predicting Adverse Cardiovascular Events for Tyrosine Kinase Inhibitors from Molecular Features
Anders Dohlman BD2K-LINCS DCIC Ma’ayan Lab 11/29/16 Cardiac Effects of TK Inhibition
Hypertension high blood pressure
Hypertrophy thickened ventricular septum
Cardiomyopathy decrease in contractility
Ejection fraction decrease less blood leaving heart
Pulmonary odema buildup of fluid in the lung ACEs Bit Matrix
FAERS
+
FDA Drug Labels ELISA –– Kinase Inhibition No ACE
Cardiac Failure Decreased Ejection Fraction Hypertension
Data from Uitdehaag et al. (PLoS ONE, 2014) Random Forest Classification Scheme
Reported
Not Reported
INPUT OUTPUT – TKI signatures – ACE Predictions – Molecular features – Feature importance ELISA Canvas Analysis Least important Most important Tiles are arranged to place co-inhibited kinases adjacently. Each canvas is a torus. Any Cardiac Failure Decreased EF Hypertension
1. PDGFRA 1. ABL_E255K 1. CDK4/CycD3 1. KDR 2. PDGFRA_V561D 2. ABL 2. LKB1 2. KIT_T670I 3. FLT4 3. ARG 3. CDK9/CycT1 3. FLT1 4. KIT 4. CDK3/CycE1 4. FLT4 5. EGFR 5. RET_M918T ADR no ADR
Hypertension is predicted by VEGFRs, cKIT, RET
% Inhibition
FLT1 (VEGFR1) / promote angiogenesis & vascular development KDR (VEGFR2)
KIT –– proto-oncogene implicated in GIST, AML
RET –– cadherin family, involved in neuronal navigation ADR no ADR
Cardiac Failure is predicted by ABLs, cKIT, PDGFR
% Inhibition
ABL (ABL1) ARG (ABL2) / NRTKs, regulate cytoskeleton remodeling, motility
KIT –– proto-oncogene implicated in GIST, AML
PDGFRA –– organ development, wound healing, proliferation LINCS Transcripomics –– L1000
• Based on FLEXMAP 3D System by Luminex • Measures 1000 “landmark” genes per experiment, and uses these to infer expression of the full transcriptome – Minimally redundant – Widely expressed across cellular contexts • Over 1.5 million gene expression profiles in total – 20,413 chemical compounds – 22,119 genetic perturbations – 77 cell lines profiled 80% LINCS Transcripomics –– DToxS
• Seeks to obtain cellular signatures related to adverse effects caused by FDA-approved drugs • Four adult PromoCell cardiomyocyte cell lines – 38 drugs – 570 transcriptional experiments – 114 proteomic experiments Trace of Performance
F1 L1000
DToxS F1
Genes Trace of Performance
F1 L1000
~50
DToxS F1
~12 Genes Pathway Analysis Using Gene Set Enrichment
ACEs
M f Kinase Inhibitors
Gene Expression Enrichment Features Pathway Analysis Using Gene Set Enrichment
500 down 500 up Gene Signature
ACEs
M f Kinase Inhibitors
Gene Expression Enrichment Features Pathway Analysis Using Gene Set Enrichment
500 down 500 up Gene Signature
ACEs
M f Kinase Inhibitors
Gene Expression Enrichment Features Pathway Analysis Using Gene Set Enrichment
500 down 500 up Gene Signature
Enrichment Vector
ACEs
M f Kinase Inhibitors
Gene Expression Enrichment Features Pathway Analysis Using Gene Set Enrichment
Hypertension Cardiac Failure Decreased Ejection Fraction
Gini Pathway Analysis Using Gene Set Enrichment
Hypertension Cardiac Failure Decreased Ejection Fraction
Significant enrichment for transmembrane ion channels, particularly Ca2+ ...these channels play a fundamental role in neuromuscular signaling, muscle contraction Conclusions
I. Screening ELISA binding data to identify kinases predictive of adverse cardiac events – Cardiac Failure: ABL1, ABL2 – Decreased Ejection Fraction: cyclin-kinase complexes – Hypertension: VEGFRs, c-Kit
II. Binding of drug-resistant c-Kit mutants are stronger predictors of hypertension than the c-Kit wild-type – ATP-binding site: V654A, T670I
III. Screening of LINCS L1000, DToxS data for genetic biomarkers of adverse cardiac events – Peak performance with 12 or 50 genes, respectively
IV. Enrichment analysis of predictive genes reveals potential mechanisms of hypertension & cardiac dysfunction – Ca2+-induced mitochondrial membrane potential collapse – Potentially due to deregulation of PKA in cardiomyocytes Acknowledgements
Avi Ma’ayan Darrell Abernethy Shadia Zaman ... Qiaonan Duan Simon Koplev Zichen Wang ... The Ma’ayan Lab