Acquired Resistance to EGFR TKIs Mediated by TGFβ1/Integrin β3 Signaling in EGFR-Mutant Lung Cancer

Investigation of novel molecular mechanism is essential to develop strategies to overcome acquired resistance to EGFR tyrosine kinase inhibitors (TKI). Integrin has been demonstrated as a regulator of cancer progression. The aim of this study was to identify which specific integrins are involved and regulated in acquired resistance to EGFR TKIs in EGFR-mutant lung cancer. The expression levels of integrin subunits were examined in EGFR-mutant lung cancer cells and xenograft tumors with acquired resistance to EGFR TKIs. Manipulation of integrin beta 3 was performed to explore whether integrin beta 3 overexpression was associated with TKI resistance, anoikis resistance, EMT, and cancer sternness in resistant lung cancer. To explore the mechanism, TGF beta 1 level was examined, and TGF beta 1 inhibitor was then used. Integrin beta 3 was dramatically and consistently overexpressed in acquired gefitinib- or osimertinib-resistant lung cancer in vitro and in vivo. integrin beta 3 was also involved in the progression of lung adenocardnoma. Antagonizing integrin beta 3 increased the TKI sensitivity and delayed the occurrence of TKI resistance in vitro and in vivo, as well as suppressed proliferation, anoikis resistance, and EMT phenotype in lung cancer cells. Overexpression of integrin beta 3 was also associated with the enhanced cancer stemness that was acquired in the development of resistance and suppressed by antagonizing integrin beta 3. Mechanistically. integrin beta 3 was induced by increased TGF beta 1 levels in acquired TKI-resistant lung cancer. Our study identified the TGF beta 1/integrin beta 3 axis as a promising target for combination therapy to delay or overcome acquired resistance to EGFR TKIs in EGFR-mutant lung cancer.