TGFß1/integrin ß3 positive feedback loop contributes to acquired EGFR TKI resistance in EGFR-mutant lung cancer.

Inevitable emergence of acquired resistance to EGFR TKIs including third-generation TKI osimertinib limits their long-term efficacy in treating EGFR-mutant lung cancer. A fuller investigation of novel molecular mechanisms underlying acquired resistance is essential to develop efficacious therapeutic strategies. Consequently, we have identified a novel TGFß1/integrin ß3 loop that contributes to the occurrence of EGFR TKI-acquired resistance. EGFR TKIs dramatically and sustainably increased the expression of both TGFß1 and integrin ß3 in in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to EGFR TKIs. Previously, we reported that integrin ß3 expression was partially induced by TGFß1 in these models. Moreover, elevated TGFß1 in these models was secreted mostly from lung cancer cells. Mechanistically, TGFß1 was induced and activated by overexpressed integrin ß3, forming a positive feedback loop. More importantly, the interruption of TGFß1/integrin ß3 positive feedback loop was shown to dramatically delay the occurrence of acquired resistance and greatly improve the efficacy of EGFR TKI in treating EGFR-mutant lung cancer. Taken together, our study first demonstrated the TGFß1/integrin ß3 loop a new mechanism and target for acquired EGFR TKI resistance in EGFR-mutant lung cancer.