Looking into the toxicity potential and clinical benefits of tyrosine kinase inhibitors (TKIs)

As effective targeted agents, managing and treating certain forms of cancer, tyrosine kinase inhibitors (TKIs) have raised hopes of treating many patients whose cancer is unresponsive to conventional therapies. Indeed, some of these small-molecule inhibitors have recently received approval for treating autoimmune disorders with the potential to be a promising new anti-allergic drug. Although TKIs are usually well-tolerated and considered safe compared to cytostatic medications routinely used for cancer treatment, unexpected toxicities are not uncommon. They range from mild to even severe adverse drug reactions (ADRs). The inhibition of tyrosine kinases as mediators of the signal transduction process, distributed widely throughout different organs, comes with ADRs, including gastrointestinal (GI), hepatic, cardiovascular, dermatological, endocrine, hematological, musculoskeletal, ophthalmic, renal, respiratory, and neurological toxicity. These toxicities are either on-target, i.e., mechanism-based, or off-target, related to the inherent non-selectivity properties of TKIs, toxic metabolites, or immune reactions. Meanwhile, higher drug concentrations can cause both on- and/or off-target toxicities. Altogether, most TKIs-induced adverse events (AEs) appear to be manageable and reversible with conventional therapeutic approaches and, in some rare severe cases, by discontinuing or reducing the dose of the TKI that may harm the treatment of TKI-responsive tumors. Herein we review the incidence, the mechanism, and medical management of AEs associated with TKIs.