LB802 Whole exome sequencing of 16 psoriasis high-risk pedigrees

Abstract

Recent advances in targeted anticancer therapies have substantially improved the prognosis of several cancers. Such targeted therapies are not, however, free of side effects, but these side effects are clearly distinct from those induced by classical cytotoxic chemotherapies. This is likely so because targeted therapies are designed to interfere with specific oncogenic signaling pathways rather than to inhibit cell proliferation in general. In fact, interference with specific signaling pathways may lead to effects that mimic those associated with genetic disorders due to alterations in the corresponding signaling pathways. Here, based on clinical pictures of patients and a review of the litterature, we compare the clinical effects of treatment with BRAF-inhibitors with those of genetic RASopathies. We find a striking overlap between the inhibitor-induced, iatrogenic dermatoses with the genodermatoses seen in patients with corresponding congenital RASopathies, including keratosis pilaris, palmo-plantar hyperkeratosis of areas of pressure, verrucous papillomas, nevi efflorescence, wavy hair, sparse eyelashes/eyebrows, poor hair growth, and increased cancer risk. Interestingly, several cutaneous side effects induced by BRAF-inhibitors that are not typically found in RASopathies, such as acneiform dermatitis and vemurafenib-specific phototoxicity, persist/increase under co-treatment with a MEK inhibitor. This may account for an off-target effect, independent from the well described paradoxical activation of the MAPK pathway by BRAF-inhibitors in BRAFwt cells. We hope that such comparisons lead to a better understanding of the side effects of targeted therapies and perhaps a reassessment of their validity in our current therapeutic arsenal.