Biology subjects

Ahonen, S.

Publications and source records attributed to Ahonen, S..

3 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↗

bioRxiv2021

Gys1 antisense therapy rescues neuropathological bases of murine Lafora disease

Lafora disease is a fatal progressive myoclonus epilepsy. At root, it is due to constant acquisition of branches that are too long in a subgroup of glycogen molecules, leading them to precipitate and accumulate into Lafora bodies, which drive a neuroinflammatory response and neurodegeneration. As a potential therapy, we aimed to downregulate glycogen synthase, the enzyme responsible for glycogen branch elongation, in the diseases mouse models. We synthesized an antisense oligonucleotide (Gys1-ASO) that targets the mRNA of the brain-expressed glycogen synthase 1 gene (Gys1). We administered Gys1-ASO by intracerebroventricular injection and analyzed the pathological hallmarks of Lafora disease, namely glycogen accumulation, Lafora body formation, and neuroinflammation. Gys1-ASO prevented Lafora body formation in young mice that had not yet formed them. In older mice that already exhibited Lafora bodies, Gys1-ASO inhibited further accumulation, markedly preventing large Lafora bodies characteristic of advanced disease. Inhibition of Lafora body formation was associated with prevention of astrogliosis and strong trends towards correction of dysregulated expression of disease immune and neuroinflammatory markers. Lafora disease manifests gradually in previously healthy teenagers. Our work provides proof of principle that an antisense oligonucleotide targeting the GYS1 mRNA could prevent, and halt progression of, this catastrophic epilepsy.

neuroscience↗

bioRxiv2018

Deficiency of the E3 Ubiquitin Ligase RBCK1 Causes Diffuse Brain Polyglucosan Accumulation and Neurodegeneration

Glycogen synthesis is vital, malstructure resulting in precipitation and accumulation into neurotoxic polyglucosan bodies (PBs). One well-understood mechanism of PB generation is glycogen branching enzyme deficiency (GBED). Less understood is Lafora disease (LD), resulting from absence of the glycogen phosphatase laforin or the E3 ubiquitin ligase malin, and accumulation of hyperphosphorylated PBs. LD afforded first insight that glycogen sphericity depends on more than adequate branching activity. Unexpectedly, deficiencies of the Linear Ubiquitin Chain Assembly Complex (LUBAC) components RBCK1 and HOIP result in PBs in muscle tissues. Here we analyzed nervous system phenotypes of mice lacking RBCK1 and find profuse PB accumulations in brain and spinal cord with extensive neurodegeneration and neurobehavioral deficits. Brain glycogen in these mice is characterized by long chains and hyperphosphorylation, similar to LD. Like in LD, glycogen synthase and branching enzyme are unaltered. Regional PB distribution mirrors LD and not GBED. Perisynaptic PB localization is unlike LD or GBED. The results indicate that RBCK1 is part of a system supplementing laforin-malin in regulating glycogen architecture including in unique neuronal locales.

molecular biology↗