Suppressing nucleotide exchange to inhibit KRAS-mutant tumors
Abstract
Summary: Guanine nucleotide exchange factors (GEF) control the rate-limiting step of physiologic RAS activation. In this issue of Cancer Discovery, Hofmann and colleagues describe the discovery of a selective inhibitor targeting the GEF, SOS1, along with its preclinical effects in suppressing KRAS-mutant tumor growth. See related article by Hofmann et al., p. 142.
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The rationale for SHP2 and SOS1 inhibitors as pan-KRAS inhibitors is that several KRAS oncoproteins, including G12C, cycle between inactive and active states and rely on upstream activation and nucleotide exchange for full transforming potential.
“The rationale for pursuing SHP2 and SOS1 inhibitors as pan-KRAS inhibitors is grounded in the evidence that several (K)RAS oncoproteins, including KRASG12C, still cycle between an inactive and active state and rely on upstream activation and nucleotide exchange to exhibit their full transforming potential (9–13, 33, 34).”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [13]
A range of KRAS oncoproteins cycle between active and inactive states and require nucleotide exchange for activation.
“a range of KRAS oncoproteins cycle between their active and inactive states and remain dependent on nucleotide exchange for activation (11–13).”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [13]
Several drugs targeting KRAS indirectly are currently in development by interfering with nucleotide exchange and KRAS activation via SHP2 or SOS1 inhibition.
“Several drugs targeting KRAS indirectly are currently in development by interfering with nucleotide exchange and KRAS activation via SHP2 or SOS1 inhibition [54,55,56,57,58].”
From KRAS, a New Target for Precision Medicine in Colorectal Cancer? (2024) · cites this paper as [58]
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Self-citationThe structural basis of the activation of Ras by Sos
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Self-citationTumor adaptation and resistance to RAF inhibitors
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Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants
Hofmann, M. H., Gerlach, D., Misale, S., Petronczki, M., & Kraut, N. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1331 · Cited by 336 · see citing works
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KRAS, a New Target for Precision Medicine in Colorectal Cancer?
Boilève, A., Smolenschi, C., Lambert, A., Boige, V., Delaye, M., Camilleri, G. M., Tarabay, A., Valéry, M., Fuerea, A., Pudlarz, T., et al. (2024) · Cancers · doi:10.3390/cancers16203455 · Cited by 11 · see citing works
- Authors
- Zhao, Y., Xue, J. Y., & Lito, P.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Lito, Piro
- Venue
- Cancer Discovery
- Published
- 2021-01-01
- Volume
- 11
- Issue
- 1
- Pages
- 17-19
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W3120649072
- Cited by
- 21
- References
- 13
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 6 · 2023: 6 · 2022: 2 · 2021: 1
- FWCI
- 1.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NIH NCI (1R01CA23074501, 1R01CA23026701A1, K08CA191082-01A1, 1F30CA232549-01)
- Weill Cornell-Rockefeller-Sloan Kettering Tri-Institutional MD-PhD Program (T32GM007739)
- 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
- KRAS mutation, guanine nucleotide exchange factor, SOS1, Ras activation, small molecule inhibitors, tumor suppression, oncogenic Ras signaling
- MeSH terms
- Humans, Neoplasms, Nucleotides, Proto-Oncogene Proteins p21(ras), Guanine Nucleotide Exchange Factors, Mitogen-Activated Protein Kinase Kinases
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