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

Since their invention in the early 2000s,tyrosine kinase inhibitors(TKIs)have gained prominence as the most effective pathwaydirected 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.