Dra. Romina Girotti

Laboratorio de Inmuno Ontología Traslacional. Instituto de Biología y Medicina experimental (IBYME)

CONICET. Universidad de Buenos Aires

 BRAF is mutated in about 50% of human melanomas and treatment with BRAF or MEK inhibitors have resulted in increased progression-free and overall survival in melanoma patients. However, the majority of patients relapse after a relatively short period of disease control. Furthermore, after treatment with targeted therapy, most patients derive little benefit from immune checkpoint inhibitors. Resistance to targeted agents is driven by several mechanisms, so selecting second line therapies is challenging. Current advice includes the option to continue treatment beyond progression, but it is unclear how to select the patients that will benefit from this, so detecting disease progression early and elucidating the mechanisms of resistance to therapy will help optimise the clinical care of these patients. Treatment options are also needed for the ~50% of melanoma patients who are BRAF wild-type. We used whole exome sequencing (WES) to provide insight into the mechanisms of resistance to BRAF inhibition and identify new therapeutic strategies for BRAF wild-type melanomas. We present the case of a patient that was wild-type for V600 BRAF, but carried HRAS and Rb1 mutations, allowing us to predict that the patient’s tumour would be sensitive to the combination of a MEK inhibitor plus paclitaxel and we validated this therapy in a xenograft derived from the patient (PDX). Thus we show that genome analysis can be used to develop novel hypothesis-driven therapeutic strategies for patients and we show that these treatments can be validated in the patients’ PDXs. Finally, we describe the use of circulating tumour DNA (ctDNA) as a predictive biomarker of response to therapy and as a powerful approach to reveal and then monitor mechanisms of resistance. In summary, we are implementing a powerful combination of techniques for personalised medicine to improve clinical management of BRAF wild-type and BRAF mutant melanoma patients.