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| http://dx.doi.org/10.1111/bpa.12709 | DOI Listing |
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SMAD4 and KRAS Status Shape Cancer Cell-Stromal Crosstalk and Therapeutic Response in Pancreatic Cancer.
Cancer Res
January 2025
University of Cambridge, Cambridge, United Kingdom.
Pancreatic ductal adenocarcinoma (PDAC) contains an extensive stroma that modulates response to therapy, contributing to the dismal prognosis associated with this cancer. Evidence suggests that PDAC stromal composition is shaped by mutations within malignant cells, but most previous work has focused on pre-clinical models driven by KrasG12D and mutant Trp53. Elucidation of the contribution of additional known oncogenic drivers, including KrasG12V mutation and Smad4 loss, is needed to increase understanding of malignant cell-stroma crosstalk in PDAC.
View Article and Find Full Text PDFOncogenic mutant KRAS inhibition through oxidation at cysteine 118.
Mol Oncol
January 2025
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Italy.
Specific reactive oxygen species activate the GTPase Kirsten rat sarcoma virus (KRAS) by reacting with cysteine 118 (C118), leading to an electron transfer between C118 and nucleoside guanosine diphosphate (GDP), which causes the release of GDP. Here, we have mimicked permanent oxidation of human KRAS at C118 by replacing C118 with aspartic acid (C118D) in KRAS to show that oncogenic mutant KRAS is selectively inhibited via oxidation at C118, both in vitro and in vivo. Moreover, the combined treatment of hydrogen-peroxide-producing pro-oxidant paraquat and nitric-oxide-producing inhibitor N(ω)-nitro-l-arginine methyl ester selectively inhibits human mutant KRAS activity by inducing oxidization at C118.
View Article and Find Full Text PDFA Review of Circulating Tumor DNA (ctDNA) in Pancreatic Cancer: Ready for the Clinic?
J Gastrointest Cancer
January 2025
Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
Pancreatic ductal adenocarcinoma is a devastating disease which is associated with an increase in cancer-related death in the USA. The minority of patients are cured by surgery alone and typically require adjuvant chemotherapy in order to improve clinical outcomes. Circulating tumor DNA (ctDNA) is an emerging technology whereby microscopic levels of minimal residual disease (MRD) can be detected in the bloodstream.
View Article and Find Full Text PDFA cost-effectiveness analysis of sotorasib as second-line treatment for patients with KRAS-G12C-mutated metastatic non-small cell lung cancer (mNSCLC) in Switzerland.
Swiss Med Wkly
January 2025
Cancer Center und Research Center, Cantonal Hospital Graubünden, Chur, Switzerland.
Background And Objective: Because of the lack of effective targeted treatment options, docetaxel has long been the standard second-line therapy for patients with advanced non-small cell lung cancer, including the Kirsten rat sarcoma virus (KRAS) G12C mutation. The CodeBreak 200 trial demonstrated that sotorasib, a new drug targeting the G12C-mutated KRAS protein, modestly improved progression-free survival compared with docetaxel in patients whose cancer had progressed after receiving platinum chemotherapy and programmed cell death protein 1 (PD-1) / programmed death ligand 1 (PD-L1) inhibitors as first-line treatment. Consequently, sotorasib received temporary approval in Switzerland.
View Article and Find Full Text PDFUnleashing the Power of Covalent Drugs for Protein Degradation.
Med Res Rev
January 2025
Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
Targeted protein degradation (TPD) has emerged as a significant therapeutic approach for a variety of diseases, including cancer. Advances in TPD techniques, such as molecular glue (MG) and lysosome-dependent strategies, have shown substantial progress since the inception of the first PROTAC in 2001. The PROTAC methodology represents the forefront of TPD technology, with ongoing evaluation in more than 20 clinical trials for the treatment of diverse medical conditions.
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