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• W4280497507 endingPage "217" @default.
• W4280497507 startingPage "205" @default.
• W4280497507 abstract "Despite the discovery of RAS oncogenes in human tumor DNA 40 years ago, the development of effective targeted therapies directed against RAS has lagged behind those more successful advancements in the field of therapeutic tyrosine kinase inhibitors targeting other oncogenes such as EGFR, ALK, and ROS1. The discoveries that (1) malignant RAS oncogenes differ from their wild-type counterparts by only a single amino acid change and (2) covalent inhibition of the cysteine residue at codon 12 of KRASG12C in its inactive GDP-bound state resulted in effective inhibition of oncogenic RAS signaling and have catalyzed a dramatic shift in mindset toward KRAS-driven cancers. Although the development of allele-selective KRASG12C inhibitors has changed a treatment paradigm, the clinical activity of these agents is more modest than tyrosine kinase inhibitors targeting other oncogene-driven cancers. Heterogeneous resistance mechanisms generally result in the restoration of RAS/mitogen-activated protein kinase pathway signaling. Many approaches are being evaluated to overcome this resistance, with many combinatorial clinical trials ongoing. Furthermore, because KRASG12D and KRASG12V are more prevalent than KRASG12C, there remains an unmet need for additional therapeutic strategies for these patients. Thus, our current translational standing could be described as the end of the beginning, with additional discovery and research innovation needed to address the enormous disease burden imposed by RAS-mutant cancers. Here, we describe the development of KRASG12C inhibitors, the challenges of resistance to these inhibitors, strategies to mitigate that resistance, and new approaches being taken to address other RAS-mutant cancers." @default.
• W4280497507 created "2022-05-22" @default.
• W4280497507 creator A5019052781 @default.
• W4280497507 creator A5049294543 @default.
• W4280497507 creator A5054071251 @default.
• W4280497507 creator A5082685256 @default.
• W4280497507 date "2022-07-01" @default.
• W4280497507 modified "2023-10-15" @default.
• W4280497507 title "More to the RAS Story: KRAS^G12C Inhibition, Resistance Mechanisms, and Moving Beyond KRAS^G12C" @default.
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