ArticleBreast cancer research : BCR2022
Targeting SHP2 phosphatase in breast cancer overcomes RTK-mediated resistance to PI3K inhibitors.
Article in Breast cancer research : BCR, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 17 citations in OpenAlex.
- Enhanced mitochondrial fission promotes chemosensitivity via SHP-1 activity in triple-negative breast cancer.Molecular biology reports · 2026Article
- SHP2 in tumor-associated macrophages prompted the progression of colorectal cancer via modulating STAT3/PI3K signaling induced PD-1-mediated CAR-T cell apoptosis.Scientific reports · 2025Article
- PI3K/AKT/mTOR axis in vascular malformations: from molecular insights to targeted clinical trials.Orphanet journal of rare diseases · 2025Review
- Article
- Emerging opportunities to treat drug-resistant breast cancer: Discovery of novel small-molecule inhibitors against different targets.Frontiers in pharmacology · 2025Review
- TNO155 is a selective SHP2 inhibitor to targetHeliyon · 2024Article
- Newcastle disease virus induces clathrin-mediated endocytosis to establish infection through the activation of PI3K/AKT signaling pathway by VEGFR2.Journal of virology · 2024Article
- WWP1 inhibition increases SHP2 inhibitor efficacy in colorectal cancer.NPJ precision oncology · 2024Article
- Complex Roles ofAnnual review of cancer biology · 2024Article
- Specific knockout of macrophage SHP2 promotes macrophage M2 polarization and alleviates renal ischemia-reperfusion injury.iScience · 2024Article
- Tyrosine phosphataseFrontiers in immunology · 2024Review
- PI3K inhibition circumvents resistance to SHP2 blockade in metastatic triple-negative breast cancer.Journal of mammary gland biology and neoplasia · 2023Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundPI3K signaling is frequently activated in breast cancer and is targeted by PI3K inhibitors. However, resistance of tumor cells to PI3K inhibition, often mediated by activated receptor tyrosine kinases, is commonly observed and reduces the potency of PI3K inhibitors. Therefore, new treatment strategies to overcome resistance to PI3K inhibitors are urgently needed to boost their efficacy. The phosphatase SHP2, which plays a crucial role in mediating signal transduction between receptor tyrosine kinases and both the PI3K and MAPK pathways, is a potential target for combination treatment.
methodsWe tested combinations of PI3K and SHP2 inhibitors in several experimental breast cancer models that are resistant to PI3K inhibition. Using cell culturing, biochemical and genetic approaches, we evaluated tumor cell proliferation and signaling output in cells treated with PI3K and SHP2 inhibitors.
resultsCombination treatment with PI3K and SHP2 inhibitors counteracted both acquired and intrinsic breast cancer cell resistance to PI3K inhibition that is mediated by activated receptor tyrosine kinases. Dual PI3K and SHP2 inhibition blocked proliferation and led to sustained inactivation of PI3K and MAPK signaling, where resistant cells rapidly re-activated these pathways upon PI3K inhibitor monotreatment. In addition, we demonstrate that overexpression of SHP2 induced resistance to PI3K inhibition, and that SHP2 was frequently activated during the development of PI3K inhibitor resistance after prolonged treatment of sensitive cells.
conclusionsOur results highlight the importance of SHP2 as a player in resistance to PI3K inhibitors. Combination treatment with PI3K and SHP2 inhibitors could pave the way for significant improvements in therapies for breast cancer.
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