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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 TGFβ1/integrin β3 loop that contributes to the occurrence of EGFR TKI-acquired resistance. EGFR TKIs dramatically and sustainably increased the expression of both TGFβ1 and integrin β3 in  in vitro  and  in vivo  EGFR-mutant lung cancer models with acquired resistance to EGFR TKIs. Previously, we reported that integrin β3 expression was partially induced by TGFβ1 in these models. Moreover, elevated TGFβ1 in these models was secreted mostly from lung cancer cells. Mechanistically, TGFβ1 was induced and activated by overexpressed integrin β3, forming a positive feedback loop. More importantly, the interruption of TGFβ1/integrin β3 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 TGFβ1/integrin β3 loop a new mechanism and target for acquired EGFR TKI resistance in EGFR-mutant lung cancer.

TGFβ1/integrin β3 positive feedback loop contributes to acquired EGFR TKI resistance in EGFR-mutant lung cancer