45 research outputs found
TAS-120 overcomes resistance to atp-competitive FGFR inhibitors in patients with FGFR2 fusion–positive intrahepatic cholangiocarcinoma
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Resistance to checkpoint blockade therapy through inactivation of antigen presentation
Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1
Cationic Amphiphilic Polymers with Antimicrobial Activity for Oral Care Applications: Eradication of S. mutans Biofilm
Comparing life review writing with active control groups: Results of a feasibility study
The relationship between the academic stress levels and the different academic tracks of Grade 12 senior high students in De La Salle University-Dasmarinas for school year 2017-2018
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Co-occurring Alterations in the RAS-MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer.
PurposeAlthough patients with advanced-stage non-small cell lung cancers (NSCLC) harboring MET exon 14 skipping mutations (METex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood.Experimental designTargeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with advanced-stage METex14-mutated NSCLC.ResultsProminent co-occurring RAS-MAPK pathway gene alterations (e.g., in KRAS, NF1) were detected in NSCLCs with METex14 skipping alterations as compared with EGFR-mutated NSCLCs. There was an association between decreased MET TKI treatment response and RAS-MAPK pathway co-occurring alterations. In a preclinical model expressing a canonical METex14 mutation, KRAS overexpression or NF1 downregulation hyperactivated MAPK signaling to promote MET TKI resistance. This resistance was overcome by cotreatment with crizotinib and the MEK inhibitor trametinib.ConclusionsOur study provides a genomic landscape of co-occurring alterations in advanced-stage METex14-mutated NSCLC and suggests a potential combination therapy strategy targeting MAPK pathway signaling to enhance clinical outcomes
Ligand-Enabled γ-C–H Olefination and Carbonylation: Construction of β-Quaternary Carbon Centers
Regio- and stereospecific synthesis of C-3 functionalized proline derivatives by palladium catalyzed ddirected C(sp3)–H Arylation
Functionalization of C(sp3)−H bonds at the unactivated 3-position of proline derivatives has been achieved using aryl iodides and palladium catalysis. This directly affords cis-2,3-disubstituted pyrrolidines as single stereoisomers. 3- Arylation occurs in high yield under solvent-free conditions with aminoquinoline and methoxyaminoquinoline directing groups. The latter was readily removed to give primary amide derivatives with physicochemical properties appropriate for use as fragments in drug discovery