ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2025
Synthetic Lethality of SHP2 and XIAP Suppresses Proliferation and Metastasis in KRAS-mutant Nonsmall Cell Lung Cancer.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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The trial behind it
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Who cites it
9 citing papers in PubMed.
- Exosome-like nanoparticles derived fromInternational journal of pharmaceutics: X · 2026Article
- SHP-2 Expression Is a Positive Prognostic Biomarker in Non-Small-Cell Lung Carcinoma: Association with KRAS Mutation and Prolonged Survival.Pathophysiology : the official journal of the International Society for Pathophysiology · 2026Article
- SHP2 as a pivotal modulator of the tumor microenvironment in gastrointestinal cancers: from mechanisms to targeted therapies.Journal of translational medicine · 2026Review
- Article
- Inhibition of PRMT5 triggers synthetic lethality in ARID1A-deficient endometrial cancer by promoting aberrant R-loop accumulation.Molecular cancer · 2026Article
- Guanine Nucleotide Exchange Factors and Small GTPases: Their Regulation and Functions, Diseases, and Therapeutic Targets.MedComm · 2025Review
- Dissecting the METTL3/STC2 axis in colorectal cancer: implications for drug resistance and metastasis.Cell biology and toxicology · 2025Article
- Synthetic Lethality of SHP2 and XIAP Suppresses Proliferation and Metastasis in KRAS-mutant Nonsmall Cell Lung Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The novel functions of chemokines in lung cancer progression.Frontiers in immunology · 2025Review
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Authors and funding
9 authors.
Funding
Abstract
Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are associated with poor prognosis and poor response to standard therapeutic regimens in patients with nonsmall cell lung cancer (NSCLC). Identification of novel synthetic lethal partners in oncogenic KRAS is an alternative therapeutic strategy for KRAS-mutant malignancies. After high-throughput screening against a preclinical/clinical compound library, embelin, a known X-linked inhibitor of apoptosis protein (XIAP) inhibitor, specifically inhibits the catalytic activity and phosphorylation of Src homology domain 2 containing tyrosine phosphatase 2 (SHP2) in KRAS-mutant NSCLC cells. Pharmacological inhibition and genetic knockdown of XIAP and SHP2 induce synthetic lethality in KRAS-mutated NSCLC cells and xenograft animal models. Mechanistically, dual inhibition of XIAP and SHP2 by embelin lessens the proliferation and metastasis, activates senescence and endogenous apoptosis, inhibits cancer-related RAS/mitogen-activated protein kinase (MAPK), phosphoinositide-3-kinase (PI3K)/AKT, Janus kinase/signal transducers and activators of transcription (JAK/STAT), wingless-related integration site (Wnt), and nuclear factor kappa B (NF-κB) signaling pathways, and overcomes compensatory feedback in the MAPK signals through the modulation of mitogen-inducible gene-6 (MIG-6) and SPROUTY2 (SPRY2). Collectively, SHP2 and XIAP are potential synthetic lethal partners, and embelin warrants further development as a novel therapeutic option for alleviating KRAS-mutant NSCLC by cotargeting SHP2 and XIAP.
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