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AGER-dependent macropinocytosis drives resistance to KRAS-G12D-targeted therapy in advanced pancreatic cancer.
Sci Transl Med
January 2025
Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Pancreatic ductal adenocarcinoma (PDAC) driven by the mutation presents a formidable health challenge because of limited treatment options. MRTX1133 is a highly selective and first-in-class KRAS-G12D inhibitor under clinical development. Here, we report that the advanced glycosylation end product-specific receptor (AGER) plays a key role in mediating MRTX1133 resistance in PDAC cells.
View Article and Find Full Text PDFPrecision Medicine in Colorectal Cancer: Targeted Therapies and Biomarker Insights.
Curr Cancer Drug Targets
January 2025
Amity School of Pharmaceutical Sciences, Amity University, Mohali, Punjab, India.
The current review delves into the transformative role of precision medicine in addressing Colorectal Cancer [CRC], a pressing global health challenge. It examines closely signalling pathways, genetic and epigenetic modifications, and microsatellite in-stability. The primary focus is on elucidating biomarkers revolutionizing CRC diagnosis and treatment.
View Article and Find Full Text PDFMolecular and functional profiling unravels targetable vulnerabilities in colorectal cancer.
Mol Oncol
January 2025
Division of Molecular Genome Analysis, German Cancer Research Center, Heidelberg, Germany.
Colorectal cancer (CRC) patients with microsatellite-stable (MSS) tumors are mostly treated with chemotherapy. Clinical benefits of targeted therapies depend on mutational states and tumor location. Many tumors carry mutations in KRAS proto-oncogene, GTPase (KRAS) or B-Raf proto-oncogene, serine/threonine kinase (BRAF), rendering them more resistant to therapies.
View Article and Find Full Text PDFDesign, Structure Optimization, and Preclinical Characterization of JAB-21822, a Covalent Inhibitor of KRAS.
J Med Chem
January 2025
Chief executive officer, Jacobio Pharmaceuticals Group Co., Ltd., Beijing100176, P. R. China.
KRAS is the most frequently mutated driver oncogene in human cancer, and KRAS mutation is commonly found in non-small-cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). Inhibitors that covalently modify the mutated codon 12 cysteine have completed proof-of-concept studies in the clinic. Here, we describe structure-based design and cocrystal-aided drug optimization of a series of compounds with the 1,8-naphthyridine-3-carbonitrile scaffold.
View Article and Find Full Text PDFA single-cell atlas of normal and KRASG12D-malformed lymphatic vessels.
JCI Insight
January 2025
Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America.
Somatic activating mutations in KRAS can cause complex lymphatic anomalies (CLAs). However, the specific processes that drive KRAS-mediated CLAs have yet to be fully elucidated. Here, we used single-cell RNA sequencing to construct an atlas of normal and KrasG12D-malformed lymphatic vessels.
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