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

TIAM2 Contributes to Osimertinib Resistance, Cell Motility, and Tumor-Associated Macrophage M2-like Polarization in Lung Adenocarcinoma

“…Based on our research and that of other scholars, [ 67 , 68 ], we hypothesize that overexpression of TIAM2 may mediate osimertinib resistance by activating the PI3K/Akt/mTOR signaling pathway to induce M2-like TAM polarization, and thus there is a potential role for TIAM2 in tumor immunotherapy and targeted therapy with osimertinib. In addition, combination treatment modalities of immunotherapy and targeted therapy have provided significant survival benefits in the treatment of advanced NSCLC patients [ 69 ].…”

A strategy to overcome EGFR p.T790M cis p.L792F induced resistance to osimertinib

“…In fact, the change of amminoacid in codon 792 strongly diminishes the affinity of osimertinib with the EGFR protein and is crucial to osimertinib resistance. 6 This mechanism seems to be related to the modification within tumor microenviroment (TME). The Authors showed that EGFR exon 20 p.L792F in cis with EGFR exon 20 p.T790M point mutation determines an upregulation of Jak and STAT3 phosphorylation and amplified IL-4 production.…”

“…As a consequence, M2 macrophages polarization is promoted within TME, 9 resulting in osimertinib resistance. 6 …”

“…5 In this article of eBioMedicine, Sun and colleagues focused the attention on the role of acquired EGFR exon 20 p.L792F and the specific molecular mechanism by which this alteration induced resistance to osimertinib. 6 As a general rule, EGFR exon 20 p.L792F point mutation is generally found in cis with the EGFR exon 20 p.T790M, and according to the University of Texas MD Anderson Lung Cancer Moonshot GEMINI and Moffitt Cancer Center lung cancer databases, up to 26% of EGFR exon 20 p. L792X point mutations were discovered in EGFR exon 20 p.T790M positive patients treated with osimertinib. 7 Overall, EGFR exon 20 p.L792F point mutation inhibits the interaction between osimertinib and EGFR protein.…”

“…As a consequence, M2 macrophages polarization is promoted within TME, 9 resulting in osimertinib resistance. 6 The identification of this mechanism may lead to the development of specific drugs useful in the treatment of advanced stage NSCLC patients who develop resistance after osimertinib administration. In particular, drugs able to target STAT3 with a subsequent inhibition of IL4 secretion and thus blocking M2 macrophages polarization may be adopted in this patient to overcome osimertinib resistance.…”