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Preprint WatchMildSeptember 9th, 2026

eIF4A inhibition disrupts resistance-associated translational and metabolic programs in BRAF-mutant melanoma

Schcolnik-Cabrera, A.; Takdenti, M.; Sadr Hashemi Nejad, A.; Nouhi, Z.; St-Amand, S.; Capdevielle, C.; Issa, D.; Riaud, M.; Rose, A. A. N.; Khacho, M.; Mallette, F. A.; Roffe, M.; Alain, T.; Topisirovic, I.; Hulea, L.

Reports that eIF4A-dependent mRNA translation is a shared vulnerability of BRAF inhibitor-resistant melanoma, with the eIF4A inhibitor CR-1-31-B reducing nascent protein synthesis, lowering BCL-2, CDK4 and cyclin D3, and inducing apoptosis regardless of BRAF inhibitor responsiveness.

Mild contradiction

1 prior failure

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

The claim is that resistance to BRAF-directed therapy converges on translational and metabolic programs that can be reached through eIF4A rather than through deeper MAPK blockade. The Claidex record holds one BRAF failure, brimarafenib-mirdametinib-braf-melanoma-phase1-2-tolerability-termination, which stopped on tolerability of a combination designed to press harder on the same pathway. That pairing is worth noting because it is the second time in this target's short record that the limiting factor was the tolerability of stacked pathway inhibition rather than the absence of a biological rationale. A programme adopting the eIF4A hypothesis inherits the same design question, which is whether adding a translation inhibitor to a MAPK inhibitor produces a combination window any wider than the one that stopped the earlier trial. The flag is MILD because the single documented failure was a safety termination.

Abstract excerpt

Acquired resistance to mitogen-activated protein kinase (MAPK) pathway inhibitors remains a major barrier to durable control of BRAF-mutant melanoma. Although resistance mechanisms are heterogeneous, they converge on adaptive programs that support survival, phenotypic plasticity, and metabolic fitness. We asked whether eukaryotic translation initiation factor 4A (eIF4A)-dependent mRNA translation represents a shared vulnerability of kinase inhibitor-resistant melanoma. Using matched BRAFV600E A375 and BRAF inhibitor-resistant A375R cells together with additional melanoma models, we integrated pharmacological and functional assays with polysome-associated RNA sequencing, quantitative proteomics, bioenergetic profiling, metabolomics, [U-13C5]glutamine tracing, and xenograft studies. Melanoma cells remained sensitive to multiple eIF4A inhibitors regardless of their responsiveness to BRAF inhibition. The eIF4A inhibitor CR-1-31-B rapidly reduced nascent protein synthesis when used alone in A375 cells and when added to the BRAF inhibitor PLX4032 in A375R cells; it also reduced BCL-2, CDK4, and cyclin D3 abundance, suppressed clonogenic growth, and induced apoptosis. Integrated analysis showed that acquired resistance involved broad RNA-abundance remodeling with superimposed changes in translational efficiency and buffering, affecting survival, extracellular-matrix and plasticity programs, and mitochondrial and metabolic functions. In resistant cells, CR-1-31-B induced early transcript-selective translational changes, accompanied at later time points by RNA-abundance and proteome remodeling. Publicly annotated 5' untranslated regions (5'UTRs) of CR-1-31-B-sensitive transcripts were enriched for purine-rich sequence architecture and local structural complexity. eIF4A inhibition preferentially attenuated the expression of proteins acquired during resistance and imposed a lower-output metabolic state in sensitive and resistant cells, reducing tricarboxylic-acid-cycle and pentose-phosphate-pathway metabolite pools and restricting intracellular glutamine-carbon transfer downstream of uptake. In A375 xenografts, CR-1-31-B delayed tumor growth, while its combination with PLX4720 produced deeper and more sustained tumor control and prolonged tumor endpoint-free survival compared with PLX4720 alone. These findings show that multiple resistance-associated programs spanning signaling, cell survival, and metabolism share a dependency on eIF4A-dependent translation and provide a preclinical rationale to test whether adding eIF4A inhibition can prolong responses to MAPK-targeted therapy in melanoma.

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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.