Personalized oncology and BRAF^K601N melanoma: model development, drug discovery, and clinical correlation

Mutations in BRAF are the most prominent activating mutations in melanoma and are increasingly recognized in other cancers. There is currently no accepted treatment regimen for patients with mutant BRAF^K601N melanoma, and the study of melanoma driven by BRAF mutations at the 601 locus is lacking due to a paucity of cellular model systems. Therefore, we sought to better understand the treatment and clinical approach to patients with mutant BRAF^K601N melanoma and subsequently develop a novel personalized oncology platform for rare or treatment-refractory cancers.

We developed and characterized the first patient-derived, naturally occurring BRAF^K601N melanoma model, described herein as OHRI-MEL-13, and assessed efficacy using the Prestwick Chemical Library and select targeted therapeutics.

OHRI-MEL-13 exhibits loss of heterozygosity of BRAF, closely mimics the original tumor's gene expression profile, is tumorigenic in immune-deficient murine models, and is available for public accession through American Type Culture Collection. We present in silico modeling data, which illustrates the therapeutic failure of BRAF^V600E-targeted therapies in BRAF^K601N mutants. Our platform elucidated a unique role for MEK inhibition with cobimetinib, which resulted in short-term clinical success by reducing the metastatic burden.

Our model of BRAF^K601N-activated melanoma was developed, thoroughly characterized, and made available for public accession. This model served to demonstrate the feasibility of a novel personalized oncology platform that could be optimized at an institutional level for rare variant or treatment-refractory cancers. We also demonstrate the clinical utility of monotherapy MEK inhibition in a case of BRAF^K601N melanoma.