Cardiotoxicity of the new cancer therapeutics--mechanisms of, and approaches to, the problem

Abstract

Cardiotoxicity of some targeted therapeutics, including monoclonal antibodies and small-molecule inhibitors, is a reality. Herein we will examine why it occurs, focusing on molecular mechanisms to better understand the issue. We will also examine how big the problem is and, more importantly, how big it may become in the future. We will review models for detecting cardiotoxicity in the preclinical phase. We will also focus on two key areas that drive cardiotoxicity: multitargeting and the inherent lack of selectivity of ATP-competitive antagonists. Finally, we will examine the issue of reversibility and discuss possible approaches to keeping patients on therapy.

Figure 1

Mechanisms of inhibition of receptor tyrosine kinase activity by monoclonal antibodies (mAbs) vs. small molecule tyrosine kinase inhibitors (TKIs). Ligand binding to receptor tyrosine kinases (RTKs) leads to receptor dimerization and activation of the intracellular tyrosine kinase domain of the receptor. Substrates are then phosphorylated, leading to cellular responses. Monoclonal antibodies (mAbs) interfere with ligand binding to receptor and/or receptor dimerization, blocking activation of the RTKs.¹⁷ TKIs do not prevent ligand binding or dimerization, but by preventing ATP from binding to the kinase domain (which is necessary for the kinase to phosphorylate substrates), they block activation of receptors and phosphorylation of substrates.

Figure 2

Her2 signaling in cardiomyocytes. In cardiomyocytes exposed to Nrg1, ERBB2/ERBB4 heterodimers form, activating two key survival pathways in the heart, ERK and Akt. Trastuzumab blocks this activation and, via multiple mechanisms including alterations in levels of Bcl-X family members, leads to decreased cardiomyocyte survival. Not shown is the possible antibody-dependent cell cytotoxicity (an immune response) that may also contribute.

Figure 3

Re-design of imatinib based on identification of the mechanisms of cardiotoxicity. Imatinib inhibits activity of Bcr-Abl, the causal fusion protein in chronic myeloid leukemia (CML), and also targets PDGFRs (not shown) and c-Kit for the treatment of GIST. In cardiomyocytes, imatinib-mediated inhibition of Abl leads to cell death via induction of the endoplasmic reticulum stress response and subsequent JNK activation. WBZ4 is an imatinib derivative that no longer inhibits Abl does inhibit c-Kit and PDGFRs. To further protect from cardiotoxicity, WBZ4 was also designed to inhibit JNK.[24]