Abstract

The mitogen-activated protein kinase (MAPK) pathway plays a key role in cell-cycle regulation and tumor progression in multiple cancers; thus, increasingly novel small molecule inhibitors (Nibs are being developed to target RAS/RAF proteins in the MAPK pathway. Dermatologic toxicities (DTs) to newer panRAS (RMC-6236) and panRAF (LXH254) are not well studied. We present DT in six patients treated with panRAS/RAF Nibs. The patients ranged from 46 to 72 years of age, with RAS-mutated tumors that included colorectal (KRASQ61H), lung (KRASG12S), pancreatic (KRASG12D and KRAS G12R), and thyroid carcinomas (NRASQ61K), and melanoma (NRASQ61R). Combination therapy with MEK/ERK (trametinib or LTT462) Nibs was recorded in two of the six patients. Two patients presented with eczematous eruption and palpable purpura, three with acneiform eruption that progressed in one patient with eczema and erosions, all of which were biopsied to better characterize these DTs.  Examination of the skin biopsies revealed folliculitis in three patients, of which was an acute folliculitis in two patients correlating with clinical appearance of an acneiform eruption. The other three patients were interpreted as dermal hypersensitivity reaction (DHR) with associated skin erosions in one patient and another with early lymphocytic vasculitis. In this cohort of patients treated with panRAS/RAF Nibs, folliculitis and DHR were the two most common histomorphologic types of DTs. These novel panRAS/RAF Nibs exhibit overlap of DTs with other Nibs (e.g., receptor tyrosine kinases) that target the MAPK pathway illustrating that disruption of this cell signaling pathway appears to promote an off-target pro-inflammatory response in susceptible patients.