Abstract
BackgroundAdditional 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).MethodsTo 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.ResultsThis 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.ConclusionsOur 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.
Highlights
Lung cancer is one of the primary causes of cancer related incidence and mortality worldwide [1], and lung adenocarcinoma (LUAD) is the most prevalent histological subtype [2,3,4]
Higher expression of SHP2 indicates poor survival and Osimertinib resistance in LUAD patients To determine whether SHP2 participates in regulating disease progression and Osimertinib resistance in LUAD patients, we first assessed the prognostic differences of LUAD patients harboring distinct levels of SHP2 mRNA
Analysis showed that high SHP2 mRNA expression of LAUD patients suffered poor overall survival (OS) (71.27 months vs. 112.67 months, p = 0.00062) and progression free survival (PFS) (21.3 months vs. 37 months, p = 0.00019) compared to patients expressing low levels of SHP2 mRNA, suggesting that SHP2 might be involved in the tumor progression of LUAD (Fig. 1A)
Summary
Lung cancer is one of the primary causes of cancer related incidence and mortality worldwide [1], and lung adenocarcinoma (LUAD) is the most prevalent histological subtype [2,3,4]. Generations of mutant EGFR targeted tyrosine kinase inhibitors (EGFR-TKIs) have impressively improved the clinical outcome of LUAD patients [10, 11]. Updated data reported that around 43.16 % T790M mutant patients are resistant to third-generation TKI, Osimertinib, which is designed to target the ATP site of EGFR with T790M mutation [16,17,18]. Exploring effective alternative approaches is therapeutically needed for the treatment of T790M mutant LUAD patients. 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 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)
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call