Kinase inhibitors and monoclonal antibodies in oncology: clinical implications

Abstract

Molecularly targeted cancer therapies, such as small-molecule kinase inhibitors and monoclonal antibodies, constitute a rapidly growing and an important part of the oncology armamentarium. Unlike conventional (cytotoxic) chemotherapeutics, targeted therapies were designed to disrupt cancer cell pathogenesis at specific biological points essential for the development and progression of the tumour. These agents were developed to disrupt specific targets with the aim of minimizing treatment burden compared with conventional chemotherapy. Nevertheless the increasingly common use of targeted therapies has revealed some unanticipated, often clinically significant toxic effects, as well as compromising effective palliative and end-of-life management approaches. Although patients and clinicians welcome improvements in cancer prognosis, these changes can also impact patient quality-of-life. Therefore, as demand for oncology expertise increases, physicians need to apprise themselves of targeted therapies and their clinical implications, including drug-specific side effects, impact on quality of life, and cost issues, especially in relation to end-of-life care. This Review provides a useful summary and guide for professionals treating patients with malignant diseases.

Mechanistic Systems Modeling to Improve Understanding and Prediction of Cardiotoxicity Caused by Targeted Cancer Therapeutics

“…Indirect reductions in K + current may possibly be mediated by Src, a tyrosine kinase that can augment current carried by K v 11.1 (Schlichter et al, 2014). Thus, dasatinib and bosutinib, which are dual inhibitors of ABL and Src, can potentially cause reduced K + current and QT prolongation (Xu et al, 2009;Gharwan and Groninger, 2015).…”

“…Overall, of the 30 TKIs currently marketed for use in the United States, 26 list serious cardiac side effects as a "black box warning" in their prescription information (FDA and CDER, 2012;Boehringer Ingelheim International GmbH, 2014;Gharwan and Groninger, 2015). The cardiac related black box warnings of TKIs can be categorized into: cardiomyopathy, arrhythmia, myocardial infarction, hypertension, and pericardial effusion, based on the specific potential adverse events listed in the package insert.…”

“…This role was based on the finding that an ERBB1 inhibitor, erlotinib, exacerbates isoproterenol-induced myocardial injury (Chen et al, 2008). Erlotinib is associated with cardiotoxicity, including cardiac arrhythmia and myocardial infarction (Gharwan and Groninger, 2015). One of the downstream pathways common to signaling through ERBB1 and ERBB2 is the lipid kinase PI3K, which in turn activates the protein kinase Akt.…”

“…Small molecule TKIs can be further subcategorized based on whether they compete with ATP for the binding pocket or interact with other regions of the protein (Force and Kolaja, 2011). Additionally, TKIs are often identified by the intended target(s) or the target specificity (Force et al, 2007;Bellinger et al, 2015;Gharwan and Groninger, 2015). The most common target groups that are used to classify TKIs include EGFR/ERBB2 inhibitors, VEGFR inhibitors, ABL inhibitors, and multi-targeted drugs that are designed to inhibit at least two different target groups such as VEGFR and ABL (see Table 1 for descriptions of the important cellular signaling proteins mentioned in the manuscript).…”

Analysis of Copy Number Loss of the ErbB4 Receptor Tyrosine Kinase in Glioblastoma

“…Mutations such as these can be exploited when developing targeted cancer therapies [1][2][3]5 . For example, because EGFR is known to be overexpressed in non-small cell lung cancer (NSCLC), the most common type of lung cancer 5,6 , and NSCLC is treated using gefitinib-a kinase inhibitor that binds to the intracellular tyrosine kinase domain of EGFR and inhibits the signaling that drives cell proliferation and survival 6 . Amplification in HER2 copy number is observed in 20-30% of breast carcinomas 1 .…”