The KRAS mutation remains the most common driver mutation in patients with non-small cell lung cancer (NSCLC) and confers a poor prognosis. Thus far, efforts to target this mutation over the last two decades have been unsuccessful. Over the past 5 years, many efforts to develop drugs that target the RAS-RAF-MEK-ERK (MAPK) pathway have resulted in enhanced understanding of the KRAS mutant NSCLC and have provided optimism that this disease can be targeted.
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http://dx.doi.org/10.1186/s40169-015-0075-0 | DOI Listing |
Transgenic Res
January 2025
Laboratory of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20, Prague 4, Czech Republic.
Proto-oncogene KRAS, GTPase (KRAS) is one of the most intensively studied oncogenes in cancer research. Although several mouse models allow for regulated expression of mutant KRAS, selective isolation and analysis of transforming or tumor cells that produce the KRAS oncogene remains a challenge. In our study, we present a knock-in model of oncogenic variant KRAS that enables the "activation" of KRAS expression together with production of red fluorescent protein tdTomato.
View Article and Find Full Text PDFCancer Res
December 2024
Rutgers, The State University of New Jersey, New Brunswick, NJ, United States.
Mutations in the exonuclease domains of the replicative nuclear DNA polymerases POLD1 and POLE are associated with increased cancer incidence, elevated tumor mutation burden (TMB), and enhanced response to immune checkpoint blockade (ICB). Although ICB is approved for treatment of several cancers, not all tumors with elevated TMB respond, highlighting the need for a better understanding of how TMB affects tumor biology and subsequently immunotherapy response. To address this, we generated mice with germline and conditional mutations in the exonuclease domains of Pold1 and Pole.
View Article and Find Full Text PDFJ Chem Inf Model
January 2025
Computer-Aided Drug Discovery, Global Discovery Chemistry, Novartis Biomedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Targeted covalent inhibition is a powerful therapeutic modality in the drug discoverer's toolbox. Recent advances in covalent drug discovery, in particular, targeting cysteines, have led to significant breakthroughs for traditionally challenging targets such as mutant KRAS, which is implicated in diverse human cancers. However, identifying cysteines for targeted covalent inhibition is a difficult task, as experimental and in silico tools have shown limited accuracy.
View Article and Find Full Text PDFExp Mol Med
January 2025
Department of Molecular Science and Technology, Ajou University, Suwon, South Korea.
Most cancer mutation profiling studies are laboratory-based and lack direct clinical application. For clinical use, it is necessary to focus on key genes and integrate them with relevant clinical variables. We aimed to evaluate the prognostic value of the dosage of the KRAS G12 mutation, a key pancreatic ductal adenocarcinoma (PDAC) variant and to investigate the biological mechanism of the prognosis associated with the dosage of the KRAS G12 mutation.
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