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Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition
Open accessAbstract
The role of KRAS, when activated through canonical mutations, has been well established in cancer1. Here we explore a secondary means of KRAS activation in cancer: focal high-level amplification of the KRAS gene in the absence of coding mutations. These amplifications occur most commonly in esophageal, gastric and ovarian adenocarcinomas2–4. KRAS-amplified gastric cancer models show marked overexpression of the KRAS protein and are insensitive to MAPK blockade owing to their capacity to adaptively respond by rapidly increasing KRAS–GTP levels. Here we demonstrate that inhibition of the guanine-exchange factors SOS1 and SOS2 or the protein tyrosine phosphatase SHP2 can attenuate this adaptive process and that targeting these factors, both genetically and pharmacologically, can enhance the sensitivity of KRAS-amplified models to MEK inhibition in both in vitro and in vivo settings. These data demonstrate the relevance of copy-number amplification as a mechanism of KRAS activation, and uncover the therapeutic potential for targeting of these tumors through combined SHP2 and MEK inhibition. Amplification of wild-type KRAS in a subset of gastroesophageal tumors drives intrinsic resistance to MAPK inhibition that can be overcome by combined targeting of MEK and SHP2.
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“Indeed, inhibition of SHP2 was recently shown to overcome RTK-driven adaptive feedback mechanisms to MEK inhibition, and enhance the efficacy of MEK inhibitor induced growth suppression in vitro and in vivo in RAS-driven cancers (27,41–44).”
From Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition (2020) · cites this paper as [44]
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In the citing paper
“Previous experiences with trametinib, a clinical MEK inhibitor have taught us that targeted inhibition of Ras downstream effectors, including MEK would inevitably trigger the relief of ERK-mediated feedback inhibition of RTK signaling, which results in adaptive Ras reactivation that heavily depends on SHP2.86”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [86]
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In the citing paper
“the inhibition of SHP2, which connects RTKs to the RAS signaling pathway and is particularly vulnerable in cancer cells with genetic alteration in KRAS, has attracted considerable attention (12, 56–59).”
From YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis (2024) · cites this paper as [59]
Experimental — accuracy not yet measuredIn the citing paper
“In these regards, SHP2 was purposed as a combinatorial target in overcoming the resistance to MEK inhibition and presumably for drugs targeting K-RasG12C.32,86,87”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [86]
In the citing paper
“These findings echo prior studies showing that inhibition of RTK-driven feedback reactivation with SHP2 inhibitors can improve the response to MEK inhibitors [107,108,109].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [109]
In the citing paper
“Recent studies in KRAS-mutant lung cancer (54, 55) and pancreatic adenocarcinoma (55), KRAS-amplified gastric carcinoma (56), and multiple other cancer models expressing mutant or wild-type KRAS (57, 58) revealed that the anti-tumor effect of MEK inhibitor treatment could be dramatically potentiated by concurrent SHP2 inhibition.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [56]
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Metadata
- Authors
- Wong, G. S., Zhou, J., Liu, J. B., Wu, Z., Xu, X., Li, T., Xu, D., Schumacher, S. E., Puschhof, J., McFarland, J., Zou, C., Dulak, A., Henderson, L., Xu, P., O’Day, E., Rendak, R., Liao, W.-L., Cecchi, F., Hembrough, T., Schwartz, S., Szeto, C., Rustgi, A. K., Wong, K.-K., Diehl, J. A., Jensen, K., Graziano, F., Ruzzo, A., Fereshetian, S., Mertins, P., Carr, S. A., Beroukhim, R., Nakamura, K., Oki, E., Watanabe, M., Baba, H., Imamura, Y., Catenacci, D., & Bass, A. J.
- Affiliations
- Dana-Farber Cancer Institute (US)
- University of Chicago Medical Center (US)
- Broad Institute (US)
- OncoPlex Diagnostics (United States) (US)
- Abramson Cancer Center (US)
- Harvard University (US)
- Medical University of South Carolina (US)
- University of Illinois Urbana-Champaign (US)
- University of Urbino (IT)
- Kumamoto University (JP)
- Kyushu University (JP)
- The Cancer Institute Hospital (JP)
- Corresponding author
- Catenacci, Daniel
- Bass, Adam J.
- ORCID
- Zhou, Jin
- Wu, Zhong
- Li, Tianxia
- Schumacher, Steven E.
- Puschhof, Jens
- McFarland, James
- Zou, Charles
- Dulak, Austin
- Henderson, Les
- Xu, Peng
- O’Day, Emily
- Hembrough, Todd
- Schwartz, Sarit
- Szeto, Christopher
- Rustgi, Anil K.
- Wong, Kwok-Kin
- Diehl, J. Alan
- Jensen, Karin
- Graziano, Francesco
- Ruzzo, Annamaria
- Fereshetian, Shaunt
- Mertins, Philipp
- Carr, Steven A.
- Beroukhim, Rameen
- Nakamura, Kenichi
- Oki, Eiji
- Watanabe, Masayuki
- Baba, Hideo
- Imamura, Yu
- Catenacci, Daniel
- Bass, Adam J.
- Venue
- Nature Medicine
- Published
- 2018-05-28
- Volume
- 24
- Issue
- 7
- Pages
- 968-977
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6039276
- OpenAlex
- W2804957989
- Semantic Scholar
- 6af671acbd44534590b63fcb147e769f8ce02fc2
- Cited by
- 266
- References
- 48
- Citations by year
- 2026: 22 · 2025: 20 · 2024: 41 · 2023: 24 · 2022: 32 · 2021: 46 · 2020: 36 · 2019: 36 · 2018: 9
- FWCI
- 11.18
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-08-09)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- CINECA IRIS Institutional Research information system (University of Urbino) (submittedVersion, cc-by-nc-nd)
- Funders
- Japan Society for the Promotion of Science (16H06259)
- National Cancer Institute (P50CA127003, P01CA098101, K23CA178203, P30CA014599)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- gastroesophageal cancer, gastric cancer, esophageal adenocarcinoma, MEK inhibition, SHP2 inhibition, SOS1, SOS2, MAPK signaling, MAPK inhibitor resistance, combination therapy, guanine nucleotide exchange factor, protein tyrosine phosphatase
- MeSH terms
- Animals, Disease Models, Animal, Esophageal Neoplasms, Gene Amplification, Humans, Piperidines, Pyridones, Pyrimidines, Pyrimidinones, Stomach Neoplasms, Proto-Oncogene Proteins p21(ras), Mitogen-Activated Protein Kinase Kinases, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 11
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