Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management

Abstract

Since their invention in the early 2000s, tyrosine kinase inhibitors (TKIs) have gained prominence as the most effective pathway-directed anti-cancer agents. TKIs have shown significant utility in the treatment of multiple hematological malignancies and solid tumors, including chronic myelogenous leukemia, non-small cell lung cancers, gastrointestinal stromal tumors, and HER2-positive breast cancers. Given their widespread applications, an increasing frequency of TKI-induced adverse effects has been reported. Although TKIs are known to affect multiple organs in the body including the lungs, liver, gastrointestinal tract, kidneys, thyroid, blood, and skin, cardiac involvement accounts for some of the most serious complications. The most frequently reported cardiovascular side effects range from hypertension, atrial fibrillation, reduced cardiac function, and heart failure to sudden death. The potential mechanisms of these side effects are unclear, leading to critical knowledge gaps in the development of effective therapy and treatment guidelines. There are limited data to infer the best clinical approaches for the early detection and therapeutic modulation of TKI-induced side effects, and universal consensus regarding various management guidelines is yet to be reached. In this state-of-the-art review, we examine multiple pre-clinical and clinical studies and curate evidence on the pathophysiology, mechanisms, and clinical management of these adverse reactions. We expect that this review will provide researchers and allied healthcare providers with the most up-to-date information on the pathophysiology, natural history, risk stratification, and management of emerging TKI-induced side effects in cancer patients.

The Status Quo of Pharmacogenomics of Tyrosine Kinase Inhibitors in Precision Oncology: A Bibliometric Analysis of the Literature

“…Our bibliometric analysis additionally reveals a steep downward trend in original experimental research productivity after 2017. A few explanations exist for this depreciation in total publications and citations, such as the surfacing of the aforementioned drug resistance [ 9 ], the emergence of monoclonal antibodies for targeted cancer therapy [ 38 ], or unforeseen issues related to the safety profile of TKIs [ 39 , 40 ]. Perhaps the declining productivity could also be attributed to the saturation of research in the field, the inadequate applicability of PGx in clinical practice, or more simply the cyclical waxing and waning nature of research interests.…”

Cardio-Oncoimmunology: Cardiac Toxicity, Cardiovascular Hypersensitivity, and Kounis Syndrome

“…Imatinib was also reported to induce or promote cardiac dysfunction manifesting with cardiac arrythmias but, overall, cardiac side effects are rare [ 62 ]. The potential mechanisms of these side effects are unclear but hypersensitivity reactions cannot be excluded [ 63 ].…”

The Role of Amino Acids in Non-Enzymatic Antioxidant Mechanisms in Cancer: A Review

“…Medicines containing this enzyme, in addition to having a positive effect in the treatment of oncology, also have a number of serious side effects. This forces scientists and physicians to look for new ways to use this approach [ 205 ].…”