Background: Additional epidermal growth factor receptor (EGFR) mutations confer the drug resistance to generations of EGFR targeted tyrosine kinase inhibitor (EGFR-TKI), which is the thorny challenge to propel the treatment of lung adenocarcinoma (LUAD) forward. In the tailored targeting era, the strategy of EGFR-TKI combined regimen was considered the promising approach to conquer the big aforesaid question. The mechanism of SHP2 involved in the cell proliferation, cytokine production, stemness maintenance and drug resistance of LUAD was not yet fully explored.Methods: To determine the impact of SHP2 on the efficacy of EGFR T790M mutant LUAD cells to Osimertinib, SHP2 was tested in Osimertinib treated LUAD cells. Cell proliferation and stemness were tested in SHP2 modified LUAD cells. RNA sequencing were performed to explore the mechanism of SHP2 promoted stemness.Results: This study demonstrated that high SHP2 indicates poor outcome of LUAD patients, and enriched in Osimertinib resistant LUAD cells. Moreover, SHP2 inhibition suppressed the cell proliferation and damaged the stemness of EGFR T790M mutant LUAD. Furthermore, SHP2 facilitates the CXCL8 secretion of EGFR T790M mutant LUAD which derived from a CXCL8-CXCR1/2 positive feedback loop that promoted the stemness and tumorigenesis. Finally, we found SHP2 inhibited ERK-AKT-NFκB and GSK3β-β Catenin pathways in EGFR T790M mutant LUAD cells, inactivation of NF-κB confers to a blockage of CXCL8-CXCR1/2 loop, and stemness limited by restricting GSK3β/β-Catenin signaling.Conclusions: Our data revealed that inhibition of SHP2 enhances the anti-cancer effect of Osimertinib in EGFR T790M mutant LUAD by blocking CXCL8-CXCR1/2 loop mediated stemness, which may provide an alternative option to promote the efficacy of osimertinib in clinic of EGFR T790M mutant LUAD.