Blockade of STAT3/IL-4 overcomes EGFR T790M-cis-L792F-induced resistance to osimertinib via suppressing M2 macrophages polarization

by Selleckchem | Jun 04 2023

Background: The mechanism of missense alteration at EGFR L792F in patients with non-small cell lung cancer resistant to osimertinib has not been sufficiently clarified. We aimed to explore the critical molecular events and coping strategies in osimertinib resistance due to acquired L792F mutation.

Methods: Circulating tumor DNA-based sequencing data of 1153 patients with osimertinib resistance were collected to illustrate the prevalence of EGFR L792F mutation. Sensitivity to osimertinib was tested with constructed EGFR 19Del/T790M-cis-L792F cell lines in vitro and in vivo. The correlation and linked pathways between M2 macrophage polarization and EGFR L792Fcis-induced osimertinib resistance were investigated. Possible interventions to suppress osimertinib resistance by targeting IL-4 or STAT3 were explored.

Findings: The concomitant EGFR L792F was identified as an independent mutation following the acquisition of T790M after osimertinib resistance, in that 5 of the 946 patients with osimertinib resistance harbored EGFR T790M-cis-L792F mutation. Transfected EGFR 19Del/T790M-cis-L792F in cell lines had decreased sensitivity to osimertinib and enhanced infiltrating macrophage with M2 polarization. Silico analyses confirmed the role of M2 polarization in osimertinib resistance induced by EGFR T790M-cis-L792F mutation. EGFR T790M-cis-L792F mutation upregulated phosphorylation of STAT3 Tyr705 and promoted its specific binding to IL4 promoter, enhancing IL-4 expression and secretion and inducing macrophage M2 polarization. Furthermore, blockade of STAT3/IL-4 (SH-4-54 or dupilumab) suppressed macrophage M2 polarization and regressed tumor sensitivity to osimertinib.

Interpretation: Our results proved that targeting EGFR T790M-cis-L792F/STAT3 Tyr705/IL-4 pathway could be a potential strategy to suppress osimertinib resistance in NSCLC.

Comments：

The study aimed to investigate the mechanism of acquired resistance to osimertinib, an EGFR tyrosine kinase inhibitor used to treat non-small cell lung cancer (NSCLC), due to the L792F mutation. The prevalence of the EGFR L792F mutation was assessed in 1153 NSCLC patients with osimertinib resistance. In vitro and in vivo experiments were conducted to test the sensitivity of constructed EGFR 19Del/T790M-cis-L792F cell lines to osimertinib. The study also explored the correlation and linked pathways between M2 macrophage polarization and EGFR L792F-cis-induced osimertinib resistance, as well as possible interventions to suppress osimertinib resistance by targeting IL-4 or STAT3.

The study found that the EGFR L792F mutation is an independent mutation following the acquisition of T790M after osimertinib resistance, with 5 out of 946 patients with osimertinib resistance harboring EGFR T790M-cis-L792F mutation. The transfected EGFR 19Del/T790M-cis-L792F cell lines had decreased sensitivity to osimertinib and enhanced infiltrating macrophage with M2 polarization. The study confirmed the role of M2 polarization in osimertinib resistance induced by the EGFR T790M-cis-L792F mutation. The EGFR T790M-cis-L792F mutation upregulated phosphorylation of STAT3 Tyr705 and promoted its specific binding to IL4 promoter, enhancing IL-4 expression and secretion and inducing macrophage M2 polarization. Blocking STAT3/IL-4 (with SH-4-54 or dupilumab) suppressed macrophage M2 polarization and regressed tumor sensitivity to osimertinib.

In conclusion, the study suggests that targeting the EGFR T790M-cis-L792F/STAT3 Tyr705/IL-4 pathway could be a potential strategy to suppress osimertinib resistance in NSCLC.