Biology subjects

Ast, A.

Publications and source records attributed to Ast, A..

3 recordsLinked to original sources

bioRxiv2025

Modeling acquired TKI resistance and effective combination therapeutic strategies in murine RET+ lung adenocarcinoma

RET gene rearrangements yield oncogenic fusion proteins that drive a subset of lung adenocarcinomas (LUAD). The tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib are approved therapies for RET+ lung cancers and have markedly improved clinical outcomes in these patients, but acquired resistance remains a hurdle to their durable management. Using a recently developed murine model of RET+ lung cancer driven by a Trim24-Ret fusion protein, two Trim24-Ret cell lines (TR.1 and TR.2) were established. Orthotopic lung tumors generated by transplantation of these cell lines initially respond to selpercatinib followed by prompt progression within [~]3 weeks of initiating TKI treatment. Cell lines derived from the selpercatinib-resistant TR.1 and TR.2 tumors exhibited in vitro sensitivity to MET and ERBB-targeted TKIs, indicating acquired bypass signaling through these receptor tyrosine kinases. Moreover, the selpercatinib-resistant TR.1 and TR.2 cell lines exhibited increased sensitivity to MEK and PTPN11 inhibitors relative to the parental cell lines, indicating a greater dependence on MAPK pathway signaling. The TKI-resistant cell lines showed no evidence for MET gene amplification, but exhibited varied induction of multiple genes that function within MET and ERBB2:ERBB4 interaction networks including ligands (HGF, NRG1), adaptors (GAB1) and co-receptors (NRP1). Consistent with an important role for MET signaling in driving acquired selpercatinib resistance, mice bearing orthotopic lung tumors derived from TR.1 or TR.2 cells that had progressed on selpercatinib treatment underwent significant re-shrinkage upon co-treatment with the MET inhibitor, crizotinib, although progression re-occurred. By contrast, upfront treatment with selpercatinib and crizotinib in orthotopic tumors yielded complete elimination of 78% of TR.1 tumors and a prolonged duration of response in TR.2 tumors. The findings highlight the failings inherent in treating acquired resistance mechanisms at progression and the potential therapeutic impact of predicting and targeting dominant mechanisms of resistance prior to or early after initiating oncogene-targeting TKI treatment in RTK-driven LUAD.

cancer biology↗

bioRxiv2025

Formation of amyloid-like HTTex1 aggregates in neurons, downregulation of synaptic proteins and early mortality of Huntington's disease flies are causally linked

Amyloidogenic mutant huntingtin exon-1 (mHTTex1) protein aggregates with pathogenic polyglutamine (polyQ) tracts are the potential root cause of Huntingtons disease (HD). Here, we assessed the gain-of-function toxicity of mHTTex1 aggregation in neurons of HD transgenic flies. We show that the rate of mHTTex1 aggregation in neurons and early mortality of HD transgenic flies are correlated. We observed sequestration of key synaptic proteins into amyloid-like mHTTex1 aggregates and a concomitant decrease of their transcript levels, suggesting that progressive mHTTex1 aggregate stress in neurons leads to an impairment of synaptic function. Machine learning-based data analysis revealed that the abundance of synaptic proteins such as the vesicular monoamine transporter Vmat in the brain is predictive of fly survival. RNAi knockdown of Vmat-encoding transcripts in neurons with pathogenic amyloid-like HTTex1Q97 aggregates further shortened the lifespan of HD flies, supporting the hypothesis that mHTTex1 aggregation drives impairment of synaptic processes and pathogenesis of HD.

molecular biology↗

bioRxiv2024

Pathophysiological response in experimental trauma-related acute kidney injury

BackgroundTrauma and shock often severely affect the kidneys. This can lead to trauma-related acute kidney injury (TRAKI), which significantly increases the risk of adverse outcomes. MethodsTo study the pathophysiology of TRAKI, we developed a murine model of combined blunt thoracic trauma and pressure-controlled hemorrhage that induces mild transient TRAKI. ResultsThe mice showed early and transient increased plasma creatinine, urea, NGAL, and urine albumin, resolving 5 days after TRAKI induction. Despite normal kidney morphology, significant damage to proximal tubular cells and a loss of the brush border was observed. This included kidney stress responses, e.g., with induced heme oxygenase-1 expression in tubules. The upregulation of inflammatory mediators and kidney injury markers was followed by elevated leukocyte numbers, mainly consisting of monocytes/macrophages. Proteomic analyses revealed a distinct time course of intrarenal processes after trauma. 3D x-ray-based whole-organ histology by contrast-enhanced microcomputed tomography showed significant impairment of capillary blood flow, especially during the first day post THS, which was partly resolved by day 5. ConclusionsOur novel model of murine TRAKI has revealed previously unknown aspects of the complex temporal pathophysiological response of the kidney along the nephron after trauma and hemorrhage, which may provide mechanistic starting points for future therapeutic approaches.

pathology↗