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

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

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

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

Advanced Atherosclerosis in 20 year old treated with TKI’s (dasatinib and ponatinib) Herrmann, Joerg et al. Mayo Clinic Proceedings , Volume 90 , Issue 8 , 1167 - 1168

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?

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

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

What does ABL/Arg do? ABL1 ABL2 p190 Rho GAP + p120 RasGAP RhoA ROCK P Y 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.

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

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

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

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

What does ROCK do?

ROCK levels rise in coronary syndromes

Nitrates work through ROCK

Statins work through ROCK

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