1. Cardiotoxicity of Tyrosine Kinase Inhibitors: Novel mechanisms and implications for atherosclerosis
Ori Ben-Yehuda, MD, FACC
Clinical Trials Center
Cardiovascular Research Foundation &
Columbia University

2. I have no relevant financial relationships
ORI BEN-YEHUDA, MD
I have no relevant financial relationships

3. Kinases and Cancer
Kinases- enzymes that transfer one or more phosphate groups from ATP to specific protein or lipid substrates
Control cell signaling and diverse cellular functions
Overactivation of kinases common in cancers
~20 lipid kinases and >500 protein kinases
3 categories of commonly used KI’s
Targeting VEGF Signaling Pathway (VSP)
Targeting ABL Kinase (TKI)
Targeting the phosphoinositide 3-kinases (PI3Ks)/AKT/mammalian target of rapamycin (mTOR) signaling pathway

5. Chronic Myelogenous Leukemia (CML)
1:500 lifetime incidence
Mean age 64
15-20% of adult leukemias
Characterized by Philadelphia Chromosome
translocation t(9;22)
Creation of BCR-ABL gene

6. Advanced Atherosclerosis in 20 year old treated with TKI’s
(dasatinib and ponatinib)
Herrmann, Joerg et al.
Mayo Clinic Proceedings , Volume 90 , Issue 8 ,

7. Clinically Available BCR-ABL Kinase Inhibitors and Atherothrombotic Events
TKI
CML efficacy
Events
Comment
imatinib +
0/+
Minimal
bosutinib ++
Early follow up
dasatinib
+++
No PVD; pulmonary HTN
nilotinib 300
Similar to ponatinib
nilotinib 400
ponatinib
++++
Is there a correlation between anti-leukemic efficacy and VOE rate?

8. Comparison of TKI Target Profiles Relative to Clinically Effective Concentrations
Effective-Cave/IC50
0.25 1 4 16 64
Ponatinib
Imatinib
Nilotinib
Dasatinib
Bosutinib
Sunitinib
Regorafenib
Cabozantinib
ABL, ARG
PDGFR family
Ephrins
SRC family
VEGFR family
FGFR family
Kinases with an effective-Cave/IC50 ≥0.5 for at least 1 TKI are shown
All the BCR-ABL kinases overlap in their potency against both ABL and ARG

9. Ponatinib (Iclusig): Evidence of Atherothrombotic Events
Total Subjects 81
449
Total No. of Subjects with events 26 92
Percent with CV Events
32%
20%
Total CV Events 51
201
Coronary Revascularization (pci plus cabg) 4 34
Angina (new or progressive) 7 MI 22
PAD (new or progression) 5 20
PAD Revascularization 11 17
Acute Limb Ischemia 3 9
Stroke/TIA
Heart Failure 27
PE/Venous Thrombosis 15
CV Death

10. What does ABL/Arg do? ABL1 ABL2 p190 Rho GAP + p120 RasGAP RhoA ROCK PY
ABL and ARG both phosphorylate p190 Rho-GAP, which causes its association with p120 RasGAP. The complex inhibits RhoA. In the absence of inhibition, RhoA increases level of Rho kinase (ROCK). Thus inhibiting RhoA inhibits ROCK.
Therefore ABL and ARG together keep ROCK levels low, and the loss (or inhibition) of ABL and ARG elevates ROCK levels.

11. What does ABL/Arg loss do?
p190 Rho GAP
+ p120 RasGAP
RhoA
ROCK P Y
Ponatinib tablets

12. What does ABL/Arg loss do?
p190 Rho GAP
+ p120 RasGAP
RhoA
ROCK P Y
Ponatinib tablets

13. What does ABL/Arg loss do?
p190 Rho GAP
+ p120 RasGAP
RhoA
ROCK P Y
Ponatinib tablets

14. What does ABL/Arg loss do?
p190 Rho GAP
+ p120 RasGAP
RhoA
ROCK P Y
Ponatinib tablets

15. What does ROCK do?

16. ROCK levels rise in coronary syndromes

17. Nitrates work through ROCK

18. Statins work through ROCK

21. Summary observations
Evidence exists that in BCR-ABL inhibitors response rate and Atherothrombotic rate are correlated suggesting an on-target relationship
ABL1 and ABL2 are part of complex signaling networks, and both proteins are involved in control of Rho-ROCK signaling, acting probably as negative mediators
This has been demonstrated in fibroblasts, neurons, glioma, and epithelium, but is not extensively studied in endothelium
Inhibition of the negative regulators is predicted to result in a positive effect on ROCK expression
ROCK is convincingly involved in vascular occlusive processes
Inhibition of ROCK is therapeutic
There are a number of clinically applicable assays to test this hypothesis