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Targeted cancer therapies have fundamentally transformed the treatment of many types of cancers over the past decade, including breast, colorectal, lung, and pancreatic cancers, as well as lymphoma, leukemia, and multiple myeloma. The unique mechanisms of action of these agents have resulted in many patients experiencing enhanced tumor response together with a reduced adverse event profile as well. Toxicities do continue to occur, however, and in selected cases can be clinically challenging to manage. Of particular importance in the context of this monograph is that the pathobiology for oral mucosal lesions caused by targeted cancer therapies has only been preliminarily investigated. There is distinct need for novel basic, translational, and clinical research strategies to enhance design of preventive and therapeutic approaches for patients at risk for development of these lesions. The research modeling can be conceptually enhanced by extrapolating "lessons learned" from selected oral mucosal conditions in patients without cancer as well. This approach may permit determination of the extent to which pathobiology and clinical management are either similar to or uniquely distinct from oral mucosal lesions caused by targeted cancer therapies. Modeling associated with oral mucosal disease in non-oncology patients is thus presented in this context as well. This article addresses this emerging paradigm, with emphasis on current mechanistic modeling and clinical treatment. This approach is in turn designed to foster delineation of new research strategies, with the goal of enhancing cancer patient treatment in the future., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Oral adverse events (OAEs) associated with multitargeted tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors (mTORIs) are underestimated but frequent and novel presentations of mucosal manifestations. Because optimal antitumor activity requires maintaining the optimal dose, it is essential to avoid unintended treatment delays or interruptions., Methods: We review the reported prevalence and appearance of OAEs with TKIs and mTORIs and the current oral assessment tools commonly used in clinical trials. We discuss the correlations between OAEs and hand-foot skin reaction (HFSR) and rash., Results: The reported prevalence of oral mucositis/stomatitis of any grade is 4% for pazopanib, 28% for sorafenib, 38% for sunitinib, 41% for temsirolimus, and 44% for everolimus. Oral lesions associated with these agents have been reported to more closely resemble aphthous stomatitis than OM caused by conventional agents. In addition, these agents may result in symptoms such as oral mucosal pain, dysgeusia, and dysphagia, in the absence of clinical lesions. Because of these factors, OAEs secondary to targeted agents may be underreported. In addition, a correlation between OAEs and HFSR was identified., Conclusions: OAEs caused by TKIs and mTORIs may represent dose-limiting toxicities, especially considering the fact that even low grades of OAEs may be troubling to the patient. We discuss how these novel AEs can be assessed because current mucositis assessment tools have limitations. Prospective studies investigating the pathogenesis, risk factors, and management of OAEs are needed in order to minimize the impact on patient's health-related quality of life.