ArticleJCI insight2023
Developing SHP2-based combination therapy for KRAS-amplified cancer.
Article in JCI insight, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
8 citing papers in PubMed, 26 citations in OpenAlex.
- KRAS amplification in colorectal cancer: correlations with clinicopathological features and prognosis in patients and prediction of response to targeted therapy.Journal of translational medicine · 2025Article
- Targeting Esophageal Cancer: Promising Drugs for the Clinical Landscape and Key Knowledge Gaps.Drug design, development and therapy · 2025Review
- Clinical Advances and Challenges in Targeting KRAS Mutations in Non-Small Cell Lung Cancer.Cancers · 2024Review
- Unmutated RRAS2 emerges as a key oncogene in post-partum-associated triple negative breast cancer.Molecular cancer · 2024Article
- Past, Present, and Future Therapeutic Strategies for NF-1-Associated Tumors.Current oncology reports · 2024Review
- Targeting RAF dimers in RAS mutant tumors: From biology to clinic.Acta pharmaceutica Sinica. B · 2024Review
- CRISPRingCancers · 2024Review
- A phase 2 study of abemaciclib in patients with brain metastases secondary to non-small cell lung cancer or melanoma.Neuro-oncology advancesArticle
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Gastroesophageal adenocarcinomas (GEAs) harbor recurrent amplification of KRAS, leading to marked overexpression of WT KRAS protein. We previously demonstrated that SHP2 phosphatase, which acts to promote KRAS and downstream MAPK pathway activation, is a target in these tumors when combined with MEK inhibition. We hypothesized that SHP2 inhibitors may serve as a foundation for developing novel combination inhibitor strategies for therapy of KRAS-amplified GEA, including with targets outside the MAPK pathway. Here, we explore potential targets to effectively augment the efficacy of SHP2 inhibition, starting with genome-wide CRISPR screens in KRAS-amplified GEA cell lines with and without SHP2 inhibition. We identify candidate targets within the MAPK pathway and among upstream RTKs that may enhance SHP2 efficacy in KRAS-amplified GEA. Additional in vitro and in vivo experiments demonstrated the potent cytotoxicity of pan-ERBB kinase inhibitions in vitro and in vivo. Furthermore, beyond targets within the MAPK pathway, we demonstrate that inhibition of CDK4/6 combines potently with SHP2 inhibition in KRAS-amplified GEA, with greater efficacy of this combination in KRAS-amplified, compared with KRAS-mutant, tumors. These results suggest therapeutic combinations for clinical study in KRAS-amplified GEAs.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.