1161 10.2217/FON.13.62 © 2013 Future Medicine Ltd ISSN 1479-6694 Future Oncol. (2013) 9(8), 1161–1170 Future Oncology part of ‘Targeted’ agents: new tools in cancer therapy Translational research over the last decade has led to the development and approval of several new drugs that have improved clinical out- comes. Their ability to disrupt specific molec- ular events and signaling pathways, combined with lower systemic toxicity, distinguishes them from conventional cytotoxic chemotherapeutic agents. In general, these agents are effective in disease subgroups that depend on targeted sig- naling modules for survival, expansion and dis- semination of malignant cells. However, these signaling modules are also active in normal tissues across various organ systems, includ- ing the skin, hair and nails, leading to toxic- ity. As our understanding of potential targets and mechanisms supporting tumor develop- ment expands, novel agents, used singly or in combination, continue to enter clinical trials and practice. This development is likely to increase the incidence, patterns and severity of dermatologic adverse events (AEs) associated with targeted agents. This review will focus on therapeutic agents that inhibit signaling from the EGFR (ErbB1), and the intracellular RAS/RAF/MEK/MAPK signaling axis. We draw on a large body of clinical and labora- tory experience of drugs affecting this pathway, which informs our current view of the mecha- nisms that drive corresponding toxicities. These mechanistic insights offer fresh perspectives on countering AEs and increasing the therapeutic index of targeted agents. AEs associated with targeted agents: mechanism-based etiologies? Conventional dermatologic AEs have been asso- ciated with a diverse range of seemingly innocu- ous agents, which include antibiotics, diuretics and NSAIDS. They can range in severity from asymptomatic or mild to life-threatening (e.g., toxic epidermal necrolysis and Stevens–Johnson syndrome). The molecular epidemiology of these AEs is consistent with immune, T-cell-mediated or IgE-dependent hypersensitivity reactions that are potentially linked to certain HLA types [1]. These reactions are contingent upon immune recognition of the molecular structure of the agent, and are not attributed to the underlying molecular mechanism or drug target(s) in question. It is to be expected that, irrespective of their specific modes of action, targeted agents will cause hypersensitivity/allergic reactions, at frequencies similar to those observed with ‘nontargeted’ com- pounds. However, the AEs and skin toxicities associated with these agents may have an addi- tional dimension, intrinsic to their mechanism(s) of action and molecular target spectra shared between normal and malignant cells and tissues. A case in point is the documented role of the EGFR and several of its ligands in normal skin development and homeostasis [2]. For example, Skin toxicity of targeted cancer agents: mechanisms and intervention Viswanath Reddy Belum 1 , Hiral Fontanilla Patel 2 , Mario E Lacouture 1 & Ulrich Rodeck* 3 1 Dermatology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Rockefeller Outpatient Pavilion Suite 248, 160 East 53rd Street, New York, NY 10022, USA 2 University Medical Center of Princeton, 1 Plainsboro Road, Plainsboro, NJ 08536, USA 3 Departments of Dermatology, Cutaneous Biology & Radiation Oncology, Thomas Jefferson University, 233 S 10th Street, Philadelphia, PA 19107, USA *Author for correspondence: Tel.: +1 215 503 5622 n Fax: +1 215 503 5378 n ulrich.rodeck@jefferson.edu In recent years, targeted agents have rapidly evolved as effective tools in the clinical management of a broad range of malignant diseases. These agents disrupt molecular mechanisms and signaling modules that drive the malignant phenotype in defined subsets of malignancies. Beyond the intended cellular targets crucial to tumor growth and progression, these agents also affect signal transduction in normal cells and tissues. The resulting adverse events and their clinical management continue to change, as newer agents with an ever-increasing target spectrum are developed. We provide a succinct overview of dermatologic toxicities arising from the targeting of receptor tyrosine kinases and downstream effectors. Emergent insights into the pathomechanisms involved and the use of this knowledge base to alleviate cutaneous adverse events are discussed. Keywords n BRAF n EGFR n immunomodulation n MEK n RAS/RAF/MEK/MAPK n skin toxicity n targeted agent Review For reprint orders, please contact: reprints@futuremedicine.com