Transient Splicing-Associated Isoform Remodeling Defines Early MAPKi Resistance Adaptation in Melanoma
4 affiliations
- 1Cancer Data Science Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- 2Jim and Eleanor Randall Department of Surgery, Translational Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- 3Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL, USA
- 4Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL, USA
Abstract
A long-standing question in targeted therapy resistance is how tumor cells rapidly enter drug-tolerant states before stable resistance emerges. In BRAF-mutant melanoma, early adaptation to MAPK inhibitor (MAPKi) therapy is accompanied by profound phenotypic plasticity, yet the molecular mechanisms that enable this transition remain poorly understood. Here, we show that MAPKi adaptation is characterized by a transient transcript isoform remodeling that is largely invisible to conventional gene-expression analysis. We integrated and analyzed multiple different datasets, including bulk and single-cell RNA-seq datasets from melanoma cell lines, murine models, patient-derived xenografts and patient tumors, spanning no-treatment, on-treatment/minimal residual disease, and acquired-resistant states. We find that differential transcript usage peaks during the adaptive on-treatment phase and then is markedly attenuated when resistance was established. These dynamics were conserved across experimental systems and supported by independent exon-usage analyses. Notably, most genes undergoing differential transcript usage showed no corresponding change in total gene expression, and genes with isoform-level changes more strongly highlighted MAPKi resistance-associated pathways, including PI3K/AKT/mTOR and receptor tyrosine kinase signaling. Further, classifiers trained on cell-line transcript-usage features identified the adaptive state more accurately than gene-expression-based models in independent PDX and patient datasets. Interestingly, MAPKi-associated isoform changes recapitulated melanoblast-associated developmental splicing programs and were linked to a few key splicing regulators. Together, these findings identify an underappreciated regulatory layer connecting drug tolerance, developmental plasticity, and acquired resistance. Beyond the current context, our results suggest that comprehensively tracking isoform and splicing alterations may potentially advance our understanding of the emergence of treatment resistance in additional indications and treatment regimes.
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BibTeX
@misc{mukherjee2026transient,
title = {{Transient Splicing-Associated Isoform Remodeling Defines Early MAPKi Resistance Adaptation in Melanoma}},
author = {Sumit Mukherjee and Arashdeep Singh and Sumeet Patiyal and Hyunjeong Joo and Hyungsoo Kim and Lipika R. Pal and Kun Wang and Chi-Ping Day and Ze’ev A Ronai and Eytan Ruppin and Sridhar Hannenhalli},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.26.761932},
url = {https://www.biorxiv.org/content/10.64898/2026.10.26.761932v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Transient Splicing-Associated Isoform Remodeling Defines Early MAPKi Resistance Adaptation in Melanoma
AU - Sumit Mukherjee
AU - Arashdeep Singh
AU - Sumeet Patiyal
AU - Hyunjeong Joo
AU - Hyungsoo Kim
AU - Lipika R. Pal
AU - Kun Wang
AU - Chi-Ping Day
AU - Ze’ev A Ronai
AU - Eytan Ruppin
AU - Sridhar Hannenhalli
PY - 2026
DA - 2026/10/26
PB - bioRxiv
DO - 10.64898/2026.10.26.761932
UR - https://www.biorxiv.org/content/10.64898/2026.10.26.761932v1
AB - A long-standing question in targeted therapy resistance is how tumor cells rapidly enter drug-tolerant states before stable resistance emerges. In BRAF-mutant melanoma, early adaptation to MAPK inhibitor (MAPKi) therapy is accompanied by profound phenotypic plasticity, yet the molecular mechanisms that enable this transition remain poorly understood. Here, we show that MAPKi adaptation is characterized by a transient transcript isoform remodeling that is largely invisible to conventional gene-expression analysis. We integrated and analyzed multiple different datasets, including bulk and single-cell RNA-seq datasets from melanoma cell lines, murine models, patient-derived xenografts and patient tumors, spanning no-treatment, on-treatment/minimal residual disease, and acquired-resistant states. We find that differential transcript usage peaks during the adaptive on-treatment phase and then is markedly attenuated when resistance was established. These dynamics were conserved across experimental systems and supported by independent exon-usage analyses. Notably, most genes undergoing differential transcript usage showed no corresponding change in total gene expression, and genes with isoform-level changes more strongly highlighted MAPKi resistance-associated pathways, including PI3K/AKT/mTOR and receptor tyrosine kinase signaling. Further, classifiers trained on cell-line transcript-usage features identified the adaptive state more accurately than gene-expression-based models in independent PDX and patient datasets. Interestingly, MAPKi-associated isoform changes recapitulated melanoblast-associated developmental splicing programs and were linked to a few key splicing regulators. Together, these findings identify an underappreciated regulatory layer connecting drug tolerance, developmental plasticity, and acquired resistance. Beyond the current context, our results suggest that comprehensively tracking isoform and splicing alterations may potentially advance our understanding of the emergence of treatment resistance in additional indications and treatment regimes.
SN - 2692-8205
ER -