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bioRxiv · 10.1101/2021.07.22.453427

The MKRN1-BRAF exon4-exon9 fusion is a targetable oncogenic driver

Girtman, M. A.·Richmond, C. S.·Kenny, P. A.
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Abstract

BackgroundBRAF, when mutated at V600E, is a potent oncogenic driver in melanoma, lung and colorectal cancer with well understood signaling mechanisms and established treatment guidelines. Non-V600E mutations are less common, more functionally diverse and do not yet have clear treatment guidelines. One class of non-V600E mutations are BRAF fusion genes which typically involve the C-terminal kinase domain of BRAF joined to one of a wide repertoire of potential N-terminal fusion partners. Here, we functionally characterized an MKRN1-BRAF fusion gene which we detected in multi-gene panel sequencing of a metastatic colorectal tumor. MethodsLevels of MEK/ERK pathway activity were evaluated by western blotting in HEK293 cells ectopically expressing MKRN1-BRAF or a series of other BRAF constructs. Dependence on dimerization was evaluated by introducing a dimerization deficiency mutation and drug sensitivity was evaluated by treatment with sorafenib, dabrafenib and trametinib. ResultsMKRN1-BRAF potently activated MEK/ERK signaling and did not require dimerization for activity. Among the inhibitors evaluated, trametinib most effectively suppressed MKRN1-BRAF driven pathway activity. ConclusionOur data demonstrate that the MKRN1-BRAF fusion gene encodes an oncoprotein that strongly activates MEK/ERK signaling in a trametinib-sensitive manner.

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Girtman, M. A., Richmond, C. S., Kenny, P. A.. 2021-07-23. The MKRN1-BRAF exon4-exon9 fusion is a targetable oncogenic driver. https://doi.org/10.1101/2021.07.22.453427

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