Do the Side Effects of BRAF Inhibitors Mimic RASopathies? Alicia Sfecci, Alain Dupuy, Monica Dinulescu, Catherine Droitcourt, Henri Adamski, Smail Hadj-Rabia, Sylvie Odent, Marie-Dominique Galibert, Lise Boussemart  Journal of Investigative Dermatology  Volume 137, Issue 4, Pages 805-809 (April 2017) DOI: 10.1016/j.jid.2016.12.012 Copyright © 2016 The Authors Terms and Conditions

Figure 1 Clinical similarities between vemurafenib side effects and RASopathic phenotypes. Photographs of a 76-year-old female patient taken before (a, full face) and after 4 months of vemurafenib treatment (b, profile), compared with full-face (h) and profile (i) photographs of a 17-year-old male patient affected by cardiofaciocutaneous (CFC) syndrome with an MAP2K1 D67N germline mutation. Both patients have a partial alopecia affecting the scalp and especially the eyebrows and eyelashes. (c–g) Pictures of the same 76-year-old patient undergoing vemurafenib treatment as compared with pictures of patients with RASopathy (h–n). Note the dark brown monomorphous nevi (c, anterior part of the thighs of the vemurafenib-treated patient; j, anterior part of the trunk of a patient with Noonan syndrome, with a BRAF germline mutation) and the hyperkeratotic follicular papules on the trunk and limbs (d, right part of the trunk of the vemurafenib-treated patient; k, external part of the left arm of a patient with CFC syndrome, with a BRAF germline mutation). Also note the numerous secondary papillomas developed by the vemurafenib-treated patient (e, anterior part of the neck; f, superior part of the back) as compared with verruciform papillomas seen in adults with Costello syndrome harboring an HRAS germline mutation (l, nose and upper lip; m, forehead). Likewise, a similar yellowish hyperkeratosis of areas of pressure of the soles may be seen with the vemurafenib-treated patient (g) and the patient with HRAS mutant Costello syndrome (n). Patients gave their written permission to publish their images. Journal of Investigative Dermatology 2017 137, 805-809DOI: (10.1016/j.jid.2016.12.012) Copyright © 2016 The Authors Terms and Conditions

Figure 2 Cutaneous side effects reported in large clinical trials of BRAF and MEK inhibitors in melanoma. Graph showing the proportion (%) of patients affected by cutaneous side effects under BRAF inhibitors alone (vemurafenib or dabrafenib, dark or light blue, respectively) or in combination with MEK inhibitors (cobimetinib or trametinib, dark or light red, respectively) in large clinical trials (dabrafenib vs. dabrafenib + trametinib: COMBI-D trial, Long et al., 2015; vemurafenib: BRIM3 trial, McArthur et al., 2014; vemurafenib + cobimetinib: BRIM7 trial, Ribas et al., 2014). KA, keratoacanthoma; SCC, squamous cell carcinoma. Journal of Investigative Dermatology 2017 137, 805-809DOI: (10.1016/j.jid.2016.12.012) Copyright © 2016 The Authors Terms and Conditions

Figure 3 Model depicting the mechanism of action of BRAF inhibitors in BRAF V600E versus BRAFwt cells. Model depicting the mechanism of action of BRAF inhibitors in BRAF V600E versus BRAFwt cells. Unlike the expected inhibition of the MAPK pathway in BRAF V600E cells (a), drug binding increases wild-type RAF isoform heterodimer formation and leads to increased ERK phosphorylation in BRAFwt cells (b), as seen in RASopathies (c). In both RASopathic cells and BRAF inhibitor-exposed BRAFwt cells, MEK inhibitors have the potential to block the downstream activation of the MAPK pathway. *, activating mutation; CFC, cardiofaciocutaneous syndrome; CRAF, v-Raf murine sarcoma viral oncogene homolog C; CS, Costello syndrome; ERK, extracellular signal-regulated kinase; GDP, guanosine diphosphate; GTP, guanosine triphosphate; MAPK, mitogen-activated protein kinase; NS, Noonan syndrome; P, phosphorylation; RAF, v-Raf murine sarcoma viral oncogene; RAS, rat sarcoma viral oncogene. Bracketed proteins indicate the possible mutant proteins within the MAPK pathway for each syndrome. Journal of Investigative Dermatology 2017 137, 805-809DOI: (10.1016/j.jid.2016.12.012) Copyright © 2016 The Authors Terms and Conditions