MET-targeted therapies are clinically effective in -amplified and exon 14 deletion mutant (ex14) non-small cell lung cancers (NSCLCs), but their efficacy is limited by the development of drug resistance. Structurally distinct MET tyrosine kinase inhibitors (TKIs) (type I/II) have been developed or are under clinical evaluation, which may overcome MET-mediated drug resistance mechanisms. In this study, we assess secondary MET mutations likely to emerge in response to treatment with single-agent or combinations of type I/type II MET TKIs using TPR-MET transformed Ba/F3 cell mutagenesis assays. We found that these inhibitors gave rise to distinct secondary MET mutant profiles. However, a combination of type I/II TKI inhibitors (capmatinib and merestinib) yielded no resistant clones The combination of capmatinib/merestinib was evaluated and led to a significant reduction in tumor outgrowth compared with either MET inhibitor alone. Our findings demonstrate and that a simultaneous treatment with a type I and type II MET TKI may be a clinically viable approach to delay and/or diminish the emergence of on target MET-mediated drug-resistance mutations.
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http://dx.doi.org/10.1158/1535-7163.MCT-21-0344 | DOI Listing |
BMC Genomics
December 2024
Departments of Biology and Biomedical Engineering, and Bioinformatics Program, Boston University, 5 Cummington Mall, Boston, MA, 02215, USA.
Background: STARR-seq and other massively-parallel reporter assays are widely used to discover functional enhancers in transfected cell models, which can be confounded by plasmid vector-induced type-I interferon immune responses and lack the multicellular environment and endogenous chromatin state of complex mammalian tissues.
Results: We describe HDI-STARR-seq, which combines STARR-seq plasmid library delivery to the liver, by hydrodynamic tail vein injection (HDI), with reporter RNA transcriptional initiation driven by a minimal Albumin promoter, which we show is essential for mouse liver STARR-seq enhancer activity assayed 7 days after HDI. Importantly, little or no vector-induced innate type-I interferon responses were observed.
BMC Genomics
December 2024
Center for Quantitative Genetics and Genomics, Aarhus University, Aarhus, Denmark.
Background: Gene set tests can pinpoint genes and biological pathways that exert small to moderate effects on complex diseases like Type 2 Diabetes (T2D). By aggregating genetic markers based on biological information, these tests can enhance the statistical power needed to detect genetic associations.
Results: Our goal was to develop a gene set test utilizing Bayesian Linear Regression (BLR) models, which account for both linkage disequilibrium (LD) and the complex genetic architectures intrinsic to diseases, thereby increasing the detection power of genetic associations.
Methods Mol Biol
January 2025
Department of Pharmacology & Immunology, Medical University of South Carolina, Charleston, SC, USA.
Recent work in single-cell imaging has allowed unprecedented insight into single-cell interactions that control disease progression. However, approaches to understanding the combined extracellular and cellular microenvironment are limited. In the current protocol, we describe an approach that allows single-cell type imaging using matrix-assisted laser desorption/ionization immunohistochemistry (MALDI-IHC) of UV (ultraviolet) photocleavable mass tags combined with N-glycomic and ECM-targeted proteomic imaging from the same formalin-fixed paraffin-embedded tissue section.
View Article and Find Full Text PDFDrugs
December 2024
Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.
Arimoclomol (MIPLYFFA™), an oral small molecule that crosses the blood brain barrier and is thought to upregulate CLEAR (Coordinated Lysosomal Expression and Regulation) network genes and improve lysosomal function, is being developed by Zevra Therapeutics Inc., for the treatment of neurological manifestations of Niemann-Pick disease type C (NPC). In September 2024, arimoclomol was approved for use in combination with miglustat for the treatment of neurological manifestations of NPC in adult and pediatric patients 2 years of age and older in the USA.
View Article and Find Full Text PDFNat Cardiovasc Res
December 2024
Department of Medicine 2, RWTH Aachen University, Medical Faculty, Aachen, Germany.
Atherosclerosis is a pervasive contributor to ischemic heart disease and stroke. Despite the advance of lipid-lowering therapies and anti-hypertensive agents, the residual risk of an atherosclerotic event remains high, and developing therapeutic strategies has proven challenging. This is due to the complexity of atherosclerosis with a spatial interplay of multiple cell types within the vascular wall.
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