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Preprint WatchMildOctober 24th, 2026

RNA promotes MAPK signaling through direct interaction with BRAF

Le Barch, A.; Mennour, S.; Fabbri, L.; Sen, T.; Girault, I.; Quidville, V.; Andreani, J.; Guerois, R.; Robert, C.; Uguen, P.; Vagner, S.

RNA binds the BRAF kinase domain directly, and that binding is required for efficient BRAF:CRAF complex assembly and MEK1/2 phosphorylation, making RNA-protein interaction a determinant of MAPK pathway activation.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

This preprint reports that RNA binds a positively charged surface in the BRAF kinase domain, that depleting intracellular RNA reduces BRAF:CRAF complex assembly and MEK1/2 phosphorylation, and that a separation-of-function RNA-binding mutant selectively attenuates BRAF-dependent signaling. The claim concerns how RAF complexes assemble rather than how any single inhibitor behaves, which is why it touches the one BRAF failure in the Claidex graph. That failure, brimarafenib plus mirdametinib in BRAF and NRAS-mutant melanoma and advanced solid tumours (brimarafenib-mirdametinib-braf-melanoma-phase1-2-tolerability-termination), was stopped on a safety signal rather than on efficacy, so the preprint does not contradict a failed efficacy hypothesis. It does bear on an assumption underneath that program: that a paradox breaker combined with a MEK inhibitor acts on a RAF complex whose assembly is governed only by protein and lipid interactions. If RNA binding is a genuine input to RAF complex formation, the on-target window that combination dosing tries to hit may be set partly by a variable no current trial measures. Severity is MILD because one prior failure exists on this target and that failure was tolerability-driven.

Abstract excerpt

RNAs are increasingly recognized as direct regulators of protein function, yet whether RNA can control the activation of signaling kinases remains poorly understood. Here we identify RNA as a direct regulator of BRAF, a central kinase in the RAS-RAF-MEK-ERK (MAPK) pathway. Using complementary crosslinking and RNA-protein interaction approaches, we show that BRAF directly binds RNA in cells and that this interaction is enhanced upon MAPK pathway activation. Depletion of intracellular RNA reduces BRAF:CRAF complex assembly and impairs MEK1/2 phosphorylation, indicating that RNA contributes to RAF complex formation and MAPK signal transduction. We identify a positively charged surface within the BRAF kinase domain that mediates RNA binding. A separation-of-function RNA-binding mutant selectively attenuates BRAF-dependent MEK1/2 phosphorylation, demonstrating that RNA binding is required for efficient MAPK signaling. Moreover, artificial recruitment of the RNA-binding-deficient BRAF mutant to an RNA scaffold restores its signaling activity, supporting a direct role for RNA-mediated BRAF complex assembly. These data identify RNA as an active component of RAF kinase regulation and establish RNA-protein interactions as an additional determinant of MAPK pathway activation.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.