BRAF ^V600E Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts

Summary

The therapeutic landscape of melanoma is improving rapidly. Targeted inhibitors show promising results, but drug resistance often limits durable clinical responses. There is a need for in vivo systems that allow for mechanistic drug resistance studies and (combinatorial) treatment optimization. Therefore, we established a large collection of patient-derived xenografts (PDXs), derived from BRAF ^V600E, NRAS ^Q61, or BRAF ^WT/NRAS ^WT melanoma metastases prior to treatment with BRAF inhibitor and after resistance had occurred. Taking advantage of PDXs as a limitless source, we screened tumor lysates for resistance mechanisms. We identified a BRAF ^V600E protein harboring a kinase domain duplication (BRAF ^V600E/DK) in ∼10% of the cases, both in PDXs and in an independent patient cohort. While BRAF ^V600E/DK depletion restored sensitivity to BRAF inhibition, a pan-RAF dimerization inhibitor effectively eliminated BRAF ^V600E/DK-expressing cells. These results illustrate the utility of this PDX platform and warrant clinical validation of BRAF dimerization inhibitors for this group of melanoma patients.

Graphical Abstract

Highlights

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  Patient-derived xenograft (PDX) platform comprises 89 metastatic melanoma tumors

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  Platform includes several pre-vemurafenib and vemurafenib-resistant PDXs

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  Duplication of the BRAF ^V600E kinase domain is identified as a resistance mechanism

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  Pan-RAF dimerization inhibitor LY3009120 eliminates melanoma cells with this duplication

Abstract

Kemper et al. have built a platform composed of 89 metastatic melanoma xenografts. Using this collection as a resource, they identified a BRAF ^V600E protein harboring a duplicated kinase domain. A pan-RAF dimerization inhibitor suppresses expansion of PDXs expressing this BRAF mutant.