eIF4A inhibition disrupts resistance-associated translational and metabolic programs in BRAF-mutant melanoma
- 1University of Montreal
Abstract
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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BibTeX
@misc{schcolnikcabrera2026eif4a,
title = {{eIF4A inhibition disrupts resistance-associated translational and metabolic programs in BRAF-mutant melanoma}},
author = {A. Schcolnik-Cabrera and M. Takdenti and A. Sadr Hashemi Nejad and Z. Nouhi and S. St-Amand and C. Capdevielle and D. Issa and M. Riaud and A. A. N. Rose and M. Khacho and F. A. Mallette and M. Roffe and T. Alain and I. Topisirovic and L. Hulea},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.03.749206},
url = {https://www.biorxiv.org/content/10.64898/2026.09.03.749206v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - eIF4A inhibition disrupts resistance-associated translational and metabolic programs in BRAF-mutant melanoma
AU - A. Schcolnik-Cabrera
AU - M. Takdenti
AU - A. Sadr Hashemi Nejad
AU - Z. Nouhi
AU - S. St-Amand
AU - C. Capdevielle
AU - D. Issa
AU - M. Riaud
AU - A. A. N. Rose
AU - M. Khacho
AU - F. A. Mallette
AU - M. Roffe
AU - T. Alain
AU - I. Topisirovic
AU - L. Hulea
PY - 2026
DA - 2026/09/03
PB - bioRxiv
DO - 10.64898/2026.09.03.749206
UR - https://www.biorxiv.org/content/10.64898/2026.09.03.749206v1
AB - 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.
ER -