About this Research Topic
Protein kinase inhibitors (KIs) revolutionized the landscape of cancer treatment. The number of regulatory agency-approved KIs continues to grow, and their clinical indications are rapidly expanding to non-cancerous diseases. KIs are very often used in the management of lifelong chronic diseases. However, serious adverse reactions, particularly hepatotoxicity and cardiotoxicity, have significantly limited the clinical benefit of KIs. As of July 2019, over a quarter (13 out of 49) of FDA-approved small molecule KIs carry boxed warnings for various life-threatening toxicities in their label, which is the strongest safety warning issued by the FDA. Furthermore, the development of several new KIs were also discontinued because of severe adverse reactions during clinical trials. Unfortunately, existing knowledge on the mechanisms of KI toxicity is very limited, making it difficult to monitor or predict such detrimental reactions. This is in part due to the fact that KIs represent a heterogeneous class of drugs with a myriad of targets, making clear mechanistic conclusions challenging. The scarcity of data may also be related to the practice that the nonclinical development program of anticancer pharmaceuticals is following a specific guidance different than the non-oncology indications.
This Research Topic aims to highlight the significance of KI toxicity and provide cutting-edge advancement that may lead to better prediction or biomarker identifications for KI toxicity. We particularly welcome manuscripts dealing with these specific areas:
(1) Well-designed studies involving a large number of KIs for predicting organ toxicities using various in vitro and/or in silico models
(2) Comprehensive reviews of KI toxicity from regulatory documents, clinical trials, case reports, and other data sources
(3) Regulatory perspectives on KI toxicity
(4) Studies providing novel insights into the mechanisms of KI toxicity, such as the identification of critical pathways leading to cellular injury
(5) Investigations on the possible association between pharmacological targets and toxicity responses
(6) Systems biology approaches to assess the perturbations induced by KIs in cells and tissues, particularly in body fluids such as blood and urine that may serve as biomarkers for KI toxicity
(7) The role of drug metabolizing enzymes, drug metabolites and drug-drug interactions in KI induced organ toxicity
(8) Species differences, sex differences and age-groups differences in KI toxicity
(9) Identification of previously unrecognized serious adverse reactions associated with KIs
(10) Evaluation of the emerging human-relevant technologies such as induced pluripotent stem cells derived cell types in KI toxicity study
(11) Factors, such as genetic and epigenetic changes and preexisting diseases, that may affect a patient’s susceptibility to KI toxicity
(12) Pharmacovigilance studies on KI related adverse reactions
(13) Safety data of KIs in clinical trials and clinical practice, and patient management in preventing and alleviating KI adverse reactions
(14) Pharmacokinetic data that provide useful information for the design and interpretation of in vitro toxicity studies
Manuscripts of various types will be considered. Our preference will be given to translational research. We expect in vitro studies to closely mimic in vivo conditions regarding the concentrations tested.
Keywords: Protein kinase inhibitors, hepatotoxicity, cardiotoxicity, in vitro, biomarkers
Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.