SHP2 inhibition enhances the anticancer effect of Osimertinib in EGFR T790M mutant lung adenocarcinoma by blocking CXCL8 loop mediated stemness

Background: Additional epidermal growth factor receptor (EGFR) mutations confer the drug resistance to generations of EGFR targeted tyrosine kinase inhibitor (EGFR-TKI), posing a major challenge to developing effective treatment of lung adenocarcinoma (LUAD). The strategy of combining EGFR-TKI with other synergistic or sensitizing therapeutic agents are considered a promising approach in the era of precision medicine. Moreover, the role and mechanism of SHP2, which is involved in cell proliferation, cytokine production, stemness maintenance and drug resistance, has not been carefully explored in lung adenocarcinoma (LUAD).

Methods: To evaluate the impact of SHP2 on the efficacy of EGFR T790M mutant LUAD cells to Osimertinib, SHP2 inhibition was tested in Osimertinib treated LUAD cells. Cell proliferation and stemness were tested in SHP2 modified LUAD cells. RNA Sequencing was performed to explore the mechanism of SHP2 promoted stemness.

Results: This study demonstrated that high SHP2 expression level correlates with poor outcome of LUAD patients, and SHP2 expression is enriched in Osimertinib resistant LUAD cells. SHP2 inhibition suppressed the cell proliferation and damaged the stemness of EGFR T790M mutant LUAD. SHP2 facilitates the secretion of CXCL8 cytokine from the EGFR T790M mutant LUAD cells, through a CXCL8-CXCR1/2 positive feedback loop that promotes stemness and tumorigenesis. Our results further show that SHP2 mediates CXCL8-CXCR1/2 feedback loop through ERK-AKT-NFκB and GSK3β-β-Catenin signaling in EGFR T790M mutant LUAD cells.

Conclusions: Our data revealed that SHP2 inhibition enhances the anti-cancer effect of Osimertinib in EGFR T790M mutant LUAD by blocking CXCL8-CXCR1/2 loop mediated stemness, which may help provide an alternative therapeutic option to enhance the clinical efficacy of osimertinib in EGFR T790M mutant LUAD patients.