Predicting Adverse Cardiovascular Events for Tyrosine ... · Predicting Adverse Cardiovascular Events for Tyrosine Kinase Inhibitors from Molecular Features Anders Dohlman BD2K-LINCS

Predicting Adverse Cardiovascular Events for Tyrosine Kinase Inhibitors from

Molecular Features

Anders DohlmanBD2K-LINCS DCIC

Maayan Lab11/29/16

Cardiac Effects of TK InhibitionHypertension

high blood pressure

Hypertrophythickened ventricular septum

Cardiomyopathydecrease in contractility

Ejection fraction decreaseless blood leaving heart

Pulmonary odemabuildup of fluid in the lung

ACEsBit Matrix

FAERS

FDA Drug Labels

+

ELISA Kinase InhibitionN

o A

CE

Decreased Ejection Fraction

Cardiac Failure

Hypertension

Data from Uitdehaag et al. (PLoS ONE, 2014)

Random Forest Classification Scheme

Reported

NotReported

INPUT TKI signatures Molecular features

OUTPUT ACE Predictions Feature importance

ELISA Canvas AnalysisTiles are arranged to place co-inhibited kinases adjacently. Each canvas is a torus.

Least important Most important

Any

1. PDGFRA2. PDGFRA_V561D3. FLT44. KIT5. EGFR

Cardiac Failure

1. ABL_E255K2. ABL3. ARG

Decreased EF

1. CDK4/CycD32. LKB13. CDK9/CycT14. CDK3/CycE1

Hypertension

1. KDR2. KIT_T670I3. FLT14. FLT45. RET_M918T

TKI_canvas_arrangment_256_3.txt

NDR2PRKXMSK1MELKHIPK1PKD1PKD3NPM1-ALKALK_L1196MMST2LATS2MLK3BMXMAP3K4MLK2PKAC-bA

NDR1JAK1JAK2GSK3-aCaMK2-dDYRK1BCK1-g3NuaK1NuaK2MST1MLK1NEK2PKC-aCRIKPKC-dJAK3B

ROCK1TYK2PKN1CaMK2-bCaMK2-gPHKG2CK1-g1MARK1MARK3CaMK1-dZAP70PAK2PAK3MRCK-bACKROCK2C

PKAC-aCGK2CaMK2-aPHKG1DYRK1ACK1-g2MARK4MARK2TBK1LKB1CHK1MGC42105PKC-qDCAMKL2EGFR_T790MPIK3CA/PIK3R1D

PKAC-gMSK2DYRK2SGKErk5CDK7/CycH/MAT1DAPK1RSK4PAK5MST3PKD2CK1-eCK1-dMRCK-aEGFR_T790M_L858RHER2E

SGK2CLK1CDK9/CycT1PLK3PLK4CLK2TSSK1skMLCKRSK1RSK2CK1-aMST4MOSWEE1EGFR_L861QHER4F

BRKCDK2/CycE1JNK2JNK3JNK1BRSK1BRSK2AMPK-a1/b1/g1RSK3MINKIRAK1MAP2K2MAP2K1TNIKEGFR_L858REGFRG

WNK3RAF1BRAFp38-BHIPK2AMPK-a2/b1/g1MAP2K4FGFR4HGKFGFR3_K650EPLK1MNK1TAK1-TAB1ABL_E255KARGLYNbH

CSKSRMBRAF_V600ETAOK2EPHA7TRKBITKRETFGFR2KIT_D816VFGFR3_K650MFGFR3LYNaKITABLFYNI

EPHB3p38-AMAP2K6MAP2K3KIT_T670IMUSKFLT4RET_Y791FRET_G691SFGFR1KDRPDGFRBPDGFRA_V561DPDGFRADDR2EPHA2J

EPHB2p38-DKIT_V560GKIT_V654AHIPK3SRPK1FMSRET_S891Ap70S6KRET_M918TPDGFRA_T674IFLT3DDR1LCKEPHB1EPHA3K

FRKEPHA8EPHA5HIPK4MSSK1TRKATRKCABL_T315IFLT1METLOKSLKRONFGRHCKEPHB4L

EPHA4BTKEPHA6EPHA1MNK2LIMK1TIE2ROSMAP3K1LTKAXLINSRTYRO3BLKYESSRCM

TTKMAP2K5DYRK3CDK4/CycD3PEKTNK1AurBAurCMET_Y1235DMERFERDLKCHK2IRAK4BMPR1AMAP3K2N

NEK4p38-GCDC2/CycB1CDK6/CycD3PKRAurA/TPX2AurAIGF1REML4-ALKIRRMAP4K2FESSYKQIKPAK1TECO

IKK-bp70S6K-bCDK3/CycE1CaMK1-aCaMK4NEK9CDK2/CycA2ALK_F1174LFAKALKPYK2MAP3K3TXKSIKNEK1MAP3K5P

12345678910111213141516

Cardiac Failure

Decreased EF

Hypertension

Any

TKI_canvas_arrangment_256_3.txt

NDR2PRKXMSK1MELKHIPK1PKD1PKD3NPM1-ALKALK_L1196MMST2LATS2MLK3BMXMAP3K4MLK2PKAC-bA

NDR1JAK1JAK2GSK3-aCaMK2-dDYRK1BCK1-g3NuaK1NuaK2MST1MLK1NEK2PKC-aCRIKPKC-dJAK3B

ROCK1TYK2PKN1CaMK2-bCaMK2-gPHKG2CK1-g1MARK1MARK3CaMK1-dZAP70PAK2PAK3MRCK-bACKROCK2C

PKAC-aCGK2CaMK2-aPHKG1DYRK1ACK1-g2MARK4MARK2TBK1LKB1CHK1MGC42105PKC-qDCAMKL2EGFR_T790MPIK3CA/PIK3R1DCardiac Failure

PKAC-gMSK2DYRK2SGKErk5CDK7/CycH/MAT1DAPK1RSK4PAK5MST3PKD2CK1-eCK1-dMRCK-aEGFR_T790M_L858RHER2EDecreased EF

SGK2CLK1CDK9/CycT1PLK3PLK4CLK2TSSK1skMLCKRSK1RSK2CK1-aMST4MOSWEE1EGFR_L861QHER4FHypertension

BRKCDK2/CycE1JNK2JNK3JNK1BRSK1BRSK2AMPK-a1/b1/g1RSK3MINKIRAK1MAP2K2MAP2K1TNIKEGFR_L858REGFRGAny

WNK3RAF1BRAFp38-BHIPK2AMPK-a2/b1/g1MAP2K4FGFR4HGKFGFR3_K650EPLK1MNK1TAK1-TAB1ABL_E255KARGLYNbH

CSKSRMBRAF_V600ETAOK2EPHA7TRKBITKRETFGFR2KIT_D816VFGFR3_K650MFGFR3LYNaKITABLFYNI

EPHB3p38-AMAP2K6MAP2K3KIT_T670IMUSKFLT4RET_Y791FRET_G691SFGFR1KDRPDGFRBPDGFRA_V561DPDGFRADDR2EPHA2J

EPHB2p38-DKIT_V560GKIT_V654AHIPK3SRPK1FMSRET_S891Ap70S6KRET_M918TPDGFRA_T674IFLT3DDR1LCKEPHB1EPHA3K

FRKEPHA8EPHA5HIPK4MSSK1TRKATRKCABL_T315IFLT1METLOKSLKRONFGRHCKEPHB4L

EPHA4BTKEPHA6EPHA1MNK2LIMK1TIE2ROSMAP3K1LTKAXLINSRTYRO3BLKYESSRCM

TTKMAP2K5DYRK3CDK4/CycD3PEKTNK1AurBAurCMET_Y1235DMERFERDLKCHK2IRAK4BMPR1AMAP3K2N

NEK4p38-GCDC2/CycB1CDK6/CycD3PKRAurA/TPX2AurAIGF1REML4-ALKIRRMAP4K2FESSYKQIKPAK1TECO

IKK-bp70S6K-bCDK3/CycE1CaMK1-aCaMK4NEK9CDK2/CycA2ALK_F1174LFAKALKPYK2MAP3K3TXKSIKNEK1MAP3K5P

12345678910111213141516

ADR

no ADR

Hypertensionis predicted byVEGFRs, cKIT, RET

% Inhibition

FLT1 (VEGFR1)KDR (VEGFR2)

KIT proto-oncogene implicated in GIST, AML

RET cadherin family, involved in neuronal navigation

/ promote angiogenesis & vascular development

% Inhibition

ADR

no ADR

Cardiac Failureis predicted byABLs, cKIT, PDGFR

ABL (ABL1)ARG (ABL2)

KIT proto-oncogene implicated in GIST, AML

PDGFRA organ development, wound healing, proliferation

/ NRTKs, regulate cytoskeleton remodeling, motility

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

F1DToxS

Genes

Trace of Performance

F1

~50

L1000

F1

~12

DToxS

Genes

Pathway Analysis Using Gene Set Enrichment

Enrichment Features

M

ACEs

Kin

ase

Inhi

bito

rs

f

Gene Expression


500 up

Enrichment Features

M

ACEs

f

Gene Signature

500 down

Kin

ase

Inhi

bito

rs

Gene Expression


500 up

Enrichment Features

M

ACEs

500 down

Kin

ase

Inhi

bito

rs

Gene Expression

f

Gene Signature


500 up

Gene Expression Enrichment Features

M

ACEs

500 down

Enrichment Vector

Kin

ase

Inhi

bito

rs

f

Gene Signature

Pathway Analysis Using Gene Set EnrichmentDecreased Ejection FractionCardiac FailureHypertension

Gini

Pathway Analysis Using Gene Set EnrichmentDecreased Ejection FractionCardiac FailureHypertension

Significant enrichment for transmembrane ion channels, particularly Ca2+...these channels play a fundamental role in neuromuscular signaling, muscle contraction

ConclusionsI. 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 MaayanDarrell Abernethy

Shadia Zaman...

Qiaonan DuanSimon KoplevZichen Wang

...The Maayan Lab

Predicting Adverse Cardiovascular Events for Tyrosine Kinase Inhibitors from Molecular FeaturesCardiac Effects of TK InhibitionACEsBit MatrixELISA Kinase InhibitionRandom Forest Classification SchemeELISA Canvas AnalysisHypertensionis predicted byVEGFRs, cKIT, RETSlide Number 8LINCS Transcripomics L1000LINCS Transcripomics DToxSTrace of PerformanceTrace of PerformancePathway Analysis Using Gene Set EnrichmentPathway Analysis Using Gene Set EnrichmentPathway Analysis Using Gene Set EnrichmentPathway Analysis Using Gene Set EnrichmentPathway Analysis Using Gene Set EnrichmentPathway Analysis Using Gene Set EnrichmentConclusionsAcknowledgements

Documents

Predicting Adverse Cardiovascular Events for Tyrosine ... · Predicting Adverse Cardiovascular Events for Tyrosine Kinase Inhibitors from Molecular Features Anders Dohlman BD2K-LINCS