Biology subjects

Elenius, K.

Publications and source records attributed to Elenius, K..

6 recordsLinked to original sources

bioRxiv2024

Recurrent cancer-associated ERBB4 mutations are transforming and confer resistance to targeted therapies

Receptor tyrosine kinase ERBB4 (HER4) is frequently mutated in human cancer, and ERBB4 mutations have been identified in patients relapsing on targeted therapy. Here, we addressed the functional consequences of recurrent cancer-associated ERBB4 mutations that are located at regions important for dimer interactions and/or are paralogous to known oncogenic hotspot mutations in other ERBB genes. Eleven out of 18 analyzed mutations were transforming in cell models, thus suggesting oncogenic potential for more than half of the recurrent ERBB4 mutations. More detailed analyses of the most potent mutations, S303F, E452K and L798R, showed that they are activating, can co-operate with other ERBB receptors and are targetable with clinically available second-generation pan-ERBB inhibitors neratinib, afatinib and dacomitinib. Furthermore, the S303F mutation, together with a previously identified activating ERBB4 mutation, E715K, promoted resistance to third-generation EGFR inhibitor osimertinib in EGFR-mutant lung cancer model in vitro and in vivo. Together, these results are expected to facilitate clinical interpretation of the most recurrent cancer-associated ERBB4 mutations. The findings provide rationale for testing the efficacy of clinically used pan-ERBB inhibitors in patients harboring driver ERBB4 mutations both in the treatment-naive setting, and upon development of resistance to targeted agents.

cancer biology↗

bioRxiv2024

Phosphoproteomic analysis reveals the diversity of signaling behind ErbB inhibitor-induced phenotypes

The impact of kinase inhibitors on the phosphoproteome has been rarely investigated at a whole organism level. Here we performed a phosphoproteomic analysis in embryonic zebrafish to identify the signaling pathways perturbed by ErbB receptor tyrosine kinase inhibitors at the organism level. The phosphorylation of proteins associated with the PI3K/Akt, p38 MAPK, Notch, Hippo/Yap and {beta}-catenin signaling pathways were differentially regulated by the ErbB inhibitors. Gene set enrichment analyses indicated differential neurological and myocardial phenotypes of different ErbB inhibitors. To assess the neurological and myocardial effects, motility and ventricle growth assays were performed on zebrafish embryos treated with the ErbB and downstream signaling pathway inhibitors. The treatment with the inhibitors targeting the PI3K/Akt, p38 MAPK, and Notch signaling pathways along with the ErbB inhibitors AG1478 and Lapatinib perturbed the overall movement and ventricle wall growth of zebrafish embryos. Taken together, these results indicate that inhibitors with the same primary targets can affect different signaling pathways while eliciting similar physiological phenotypes.

cell biology↗

bioRxiv2023

Transcriptional landscape of DTP-DTEP transition reveals DUSP6 as a driver of HER2 inhibitor tolerance via Neuregulin/HER3 axis

The mechanisms promoting re-growth of dormant cancer cells under continuous tyrosine kinase inhibitor (TKI) therapy are poorly understood. Here we present transcriptional profiling of HER2+ breast cancer cells treated continuously with HER2 TKI (HER2i) therapy for 9 months. The data reveals specific gene regulatory programs associated with transition from dormant drug tolerant persister cells (DTPs) to proliferating DTEP (drug tolerant expanding persister) cells and eventually long-term resistance. Focusing on yet poorly understood phosphatases as determinants of therapy tolerance, expression of dual-specificity phosphatase DUSP6 was found inhibited in DTPs, but strongly induced upon re-growth of DTEPs. DUSP6 overexpression conferred apoptosis resistance whereas its pharmacological blockade prevented DTEP development under HER2i therapy. The DUSP6-driven HER2i tolerance was mediated by activation of neuregulin-HER3 axis, and consistent with the role of HER3 in widespread therapy tolerance, DUSP6 targeting also synergized with clinically used HER2i combination therapies. In vivo, pharmacological DUSP6 targeting induced synthetic lethal effect with HER2i in independent tumor models, and its genetic targeting reduced tumor growth in orthotopic brain metastasis model. Collectively this work provides first transcriptional landscape of DTP-DTEP transition under TKI therapy, and identify DUSP6 as a novel candidate therapy target to overcome widespread HER3-driven therapy resistance.

cancer biology↗

bioRxiv2022

Database of recurrent mutations (DORM), a web tool to browse recurrent mutations in cancers

Advances in sequencing technologies have facilitated the genetic characterization of large numbers of clinical cancer samples, leading to accumulation of extensive amounts of data. While potentially very useful for directing research and for clinical decision making, the increasing quantity of data generates challenges in its optimal management, and translation to informing clinical and research questions. Here, we present Database Of Recurrent Mutations (DORM), a database listing recurrent mutations (tissue-agnostic population frequency > 1) identified from cancer samples analyzed with whole genome or whole exome sequencing. The DORM database is a fast and feature-rich database supporting searching for several proteins, amino acid substitutions as well as queries using regular expressions.

bioinformatics↗

bioRxiv2022

STAT5b is a key effector of NRG-1/ERBB4-mediated cardiomyocyte growth

The growth factor neuregulin-1 (NRG-1) regulates hypertrophic and hyperplastic myocardial growth and is currently under clinical investigation as a treatment for heart failure. We have previously demonstrated that an isoform of the NRG-1 receptor ERBB4 (ERBB4 JM-b) expressed in cardiomyocytes selectively regulates the activation of STAT5b. To explore the role of STAT5b in NRG-1/EBBB4 mediated cardiomyocyte growth, several in vitro and in vivo models were utilized. The downregulation of NRG-1/ERBB4 signaling consistently reduced STAT5b activation and transcription of STAT5b target genes Igf1, Myc and Cdkn1a in murine in vitro and in vivo models of myocardial growth. Stat5b knock-down in primary cardiomyocytes ablated NRG-1-induced cardiomyocyte hypertrophy. Stat5b was activated during NRG-1-induced hyperplastic myocardial growth and chemical inhibition of the Nrg-1/Erbb4 pathway led to the loss of myocardial growth and Stat5 activation in zebrafish embryos. Moreover, CRISPR/Cas9-mediated knock-down of stat5b in zebrafish embryos resulted in reduced myocardial growth and heart failure as indicated by reduced ventricular ejection fraction. Dynamin-2 was discovered to control the cell surface localization of ERBB4 and the chemical inhibition of dynamin-2 downregulated NRG-1/ERBB4/STAT5b signaling in models of hypertrophic and hyperplastic myocardial growth. Finally, the activation of the NRG-1/ERBB4/STAT5b signaling pathway was explored in clinical samples representing pathological cardiac hypertrophy. The NRG-1/ERBB4/STAT5b signaling pathway was differentially regulated both at the mRNA and protein levels in the myocardium of patients with pathological cardiac hypertrophy as compared to myocardium of control subjects. These results establish the role for STAT5b, and dynamin-2 in NRG-1/ERBB4-mediated myocardial growth.

cell biology↗

bioRxiv2022

An unbiased pathway analysis (UPA) designed for multi-omics inference of cell signaling pathways

New tools for cell signaling pathway inference from multi-omics data that are independent of previous knowledge are needed. Here we propose a new de novo method, the de novo multi-omics pathway analysis (DMPA), to model and combine omics data into regulatory complexes and pathways. DMPA was validated with publicly available omics data and was found accurate in discovering protein-protein interactions, kinase substrate phosphosite relationships, transcription factor target gene relationships, metabolic reactions, epigenetic trait associations and signaling pathways. DMPA was benchmarked against existing module and network discovery and multi-omics integration methods and outperformed previous methods in module and signaling pathway discovery especially when applied to datasets with low sample sizes and zero-inflated data. Transcription factor, kinase, subcellular location and function prediction algorithms were devised for transcriptome, phosphoproteome and interactome regulatory complexes and pathways, respectively. To apply DMPA in a biologically relevant context, interactome, phosphoproteome, transcriptome and proteome data were collected from analyses carried out using melanoma cells to address gamma-secretase cleavage-dependent signaling characteristics of the receptor tyrosine kinase TYRO3. The pathways modeled with DMPA reflected both the predicted function and the direction of the predicted function in validation experiments.

systems biology↗