(165j) Non-V600E Braf Mutations in Melanoma and Their Response to Different Clinically Approved Braf Inhibitors

Melanoma is one of the deadliest skin malignancies, and its prevalence is increasing globally. Formerly thought to be a drug-resistant illness, melanoma has seen a dramatic transformation in the treatment landscape since 2011. Indeed, advances in our understanding of the immune system and its interactions with tumors, as well as ever-increasing molecular characterization of this cancer, have paved the way for immunotherapy on the one hand, and molecular target therapies on the other. The rising availability of more powerful technologies, such as Next-Generation Sequencing (NGS), as well as the growing availability of huge genetic panels, has enabled the discovery of a number of prospective therapeutic targets and the development of relevant treatments. These new therapeutic approaches improved melanoma prognosis, resulting in a 5-year survival rate of 34–43%. However, mainly because of primary and acquired drug resistance, the majority of patients will ultimately relapse, and only patients harboring a BRAF mutation, observed in about 50% of cutaneous melanoma, can receive a targeted treatment with BRAF and MEK inhibitors.

Activating mutations in the BRAF gene occur in 40-60% of melanomas with the majority of mutations resulting in V600E/K. Previous cohort studies have identified rates of non-V600E/K BRAF mutations to occur in 5-12% of patients. Despite this, there remains limited evidence characterizing the disease characteristics and outcomes of patients who harbor the non-classical BRAF mutation. In our cohort of 1000 melanoma patients, we identified three groups of patients with respect disease characteristics: a) BRAF wild type; b) BRAF V600E/K positive; and c) BRAF non-V600E/K positive. Among the last group, the most frequent BRAF mutations identified were L597S/Q, A598V, T599Dup, and K601E.

Accordingly, in this work we present the full set of results obtained from a combined computational/experimental approach for the in silico/in vitro characterization of the interaction of different clinically approved BRAF inhibitors (Dabrafenib, Vemurafenib, Encorafenib) and other investigations drugs (AZ628, PLX8394) with all these BRAF mutant isoforms. Remarkably, among all these the activating BRAF V598A variant - also found in papillary thyroid carcinoma - can be effectively inhibited by all considered inhibitors, even in the presence of activating NRAS mutations (Q61R).