Synthetic Lethality of SHP2 and XIAP Suppresses Proliferation and Metastasis in KRAS‐mutant Nonsmall Cell Lung Cancer

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.