TGFβ1/integrin β3 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 TGF beta 1/integrin beta 3 loop that contributes to the occurrence of EGFR TKI-acquired resistance. EGFR TKIs dramatically and sustainably increased the expression of both TGF beta 1 and integrin beta 3 in in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to EGFR TKIs. Previously, we reported that integrin beta 3 expression was partially induced by TGF beta 1 in these models. Moreover, elevated TGF beta 1 in these models was secreted mostly from lung cancer cells. Mechanistically, TGF beta 1 was induced and activated by overexpressed integrin beta 3, forming a positive feedback loop. More importantly, the interruption of TGF beta 1/integrin beta 3 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 TGF beta 1/integrin beta 3 loop a new mechanism and target for acquired EGFR TKI resistance in EGFR-mutant lung cancer.