Anin vivoavian model of human melanoma to perform rapid and robust preclinical studies

Abstract

AbstractMetastatic melanoma patients carrying a BRAFV600mutation can be treated with BRAF inhibitors (BRAFi), in combination with MEK inhibitors (MEKi), but innate and acquired resistance invariably occurs. Resistance can involve transcriptional- and epigenetic-based phenotypic adaptations, as yet unpredictable. Predicting patient response to targeted therapies is crucial to guide clinical decision. We describe here the development of a highly efficient patient-derived xenograft model adapted to patient melanoma biopsies, using the avian embryo as a host (AVI-PDX™). In thisin vivoparadigm, we depict a fast and reproducible tumor engraftment of patient samples within the embryonic skin, preserving key molecular and phenotypic features. We show that sensitivity and resistance to BRAFi/MEKi targeted therapies can be reliably modeled in these AVI-PDX™, as well as synergies with other drugs, such as HDACi. We further provide proof-of-concept that the AVI-PDX™models the diversity of responses of melanoma patients to BRAFi/MEKi, within days, hence positioning it as a valuable tool for the design of personalized medicine assays and for the evaluation of novel combination strategies.