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

Abstract

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.

Critical roles of PTPN family members regulated by non-coding RNAs in tumorigenesis and immunotherapy

“…Of note, PTPN11 is not only essential for lung cancer cell growth, but also confers chemotherapy resistance ( 44 ). Mechanistically, overexpression of PTPN11 increases resistance to tyrosine kinase inhibitors (TKI) in either EGFR mutant or EGFR wild-type NSCLC cells through Erk-AKT- nuclear factor kappa B (NF-κB) and GSK3β-β-Catenin signaling pathway-mediated C-X-C motif chemokine ligand 8 (CXCL8)-chemokine receptor 1/2 (CXCR1/2) feedback loop that promotes stemness and tumorigenesis ( 45 , 46 ). Moreover, PTPN11 confers cisplatin resistance to lung cancer cells through activation of the AKT-CA916798 pathway and the Ras/phosphoinositide 3-kinase (PI3K)/AKT1/survivin pathway, respectively ( 47 , 48 ).…”

Knockdown of ubiquitin-conjugating enzyme E2T (UBE2T) suppresses lung adenocarcinoma progression via targeting fibulin-5 (FBLN5)

“…Another report demonstrated that FBLN5 impedes Wnt/β-catenin signaling by inhibiting ERK activation of GSK3β in lung cancer [ 28 ]. Furthermore, a previous report showed that ERK/GSK3β pathway regulates cell proliferation and metastasis and is frequently activated in tumor tissues including LUAD [ 29 ]. Besides, UBE2T was reported to promote the activation of GSK3β pathway in nasopharyngeal carcinoma [ 30 ].…”

Cancer/testis antigen CAGE mediates Osimertinib Resistance in Non-small cell lung cancer cells and predicts poor Prognosis in Patients with Pulmonary adenocarcinoma

“…Osimertinib resistance is caused via epithelial mesenchymal transition [4]. Stemness promoted by CXCL8 feedback loop leads to osimertinib resistance [5].…”