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Improving Prospects for Targeting RAS
Abstract
RAS mutations are among the most common oncogenic drivers in human cancers, affecting nearly a third of all solid tumors and around a fifth of common myeloid malignancies, but they have evaded therapeutic interventions, despite being the focus of intense research over the last three decades. Recent discoveries lend new understanding about the structure, function, and signaling of RAS and have opened new avenues for development of much needed new therapies. We discuss the various approaches under investigation to target mutant RAS proteins. The recent development of direct RAS inhibitors specific to KRAS G12C mutations represents a landmark discovery that promises to change the perception about RAS's druggability. Multiple clinical trials targeting synthetically lethal partners and/or downstream signaling partners of RAS are underway. Novel inhibitors targeting various arms of RAS processing and signaling have yielded encouraging results in the laboratory, but refinement of the drug-like properties of these molecules is required before they will be ready for the clinic.
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“To date, however, these approaches have shown only limited clinical activity in patients with KRAS mutant cancers”
From A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution (2017) · cites this paper as Singh et al., 2015
In the citing paper
“a feature which may partially explain the heterogeneous clinical responses observed in patients treated with this combination”
From A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution (2017) · cites this paper as Singh et al., 2015
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Metadata
- Authors
- Singh, H., Longo, D. L., & Chabner, B. A.
- Affiliations
- Brigham and Women's Hospital (US)
- Venue
- Journal of Clinical Oncology
- Published
- 2015-11-01
- Volume
- 33
- Issue
- 31
- Pages
- 3650-3659
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2115099563
- Cited by
- 107
- References
- 16
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 8 · 2023: 7 · 2022: 11 · 2021: 12 · 2020: 7 · 2019: 14 · 2018: 8 · 2017: 17 · 2016: 15 · 2015: 1
- FWCI
- 1.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- RAS mutations, RAS inhibitors, KRAS G12C, synthetic lethality, Ras signaling, RAS-targeted therapy, oncogenic drivers, myeloid neoplasms, solid tumors
- MeSH terms
- Animals, Antineoplastic Agents, Clinical Trials as Topic, Humans, Mutation, Neoplasm Transplantation, Neoplasms, Genes, ras, Signal Transduction, Proto-Oncogene Proteins p21(ras), ras Proteins, Mice
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