Transglutaminase 2 induces intrinsic EGFR-TKI resistance in NSCLC harboring EGFR sensitive mutations

Abstract

The non-small cell lung cancer (NSCLC) patients with EGFR-sensitive mutations can be therapeutically treated by EGFR-TKI such as erlotinib and gefitinib. However, about 40% of individuals harboring EGFR-TKI sensitive mutations are still resistant to EGFR-TKI. And, it has been reported that both PTEN loss and NF-kappa B activation contribute to intrinsic EGFR-TKI resistance in EGFR-mutant lung cancer. Transglutaminse 2 (TG2) is post-translational modification enzyme and known to induce degradation of tumor suppressors including PTEN and I kappa B alpha with peptide cross-linking activity. Because TG2 was known as a regulator of PTEN and I kappa B alpha (NF-kappa B inhibitor) level in cytosol, we have explored if TG2 can be another key regulator to the intrinsic resistance of EGFR-TKI in the intrinsic EGFR-TKI resistant NSCLC cell. We first found that higher TG2 expression level and lower PTEN and I kappa B alpha expression levels in the intrinsic EGFR-TKI resistant NSCLC compare with EGFR-TKI sensitive NSCLC. TG2 stably expressing EGFR-TKI sensitive NSCLC cells harboring EGFR mutations showed reduction of both PTEN and IkBa and exhibited EGFR-TKI resistance. In reverse, When TG2 is downregulated by TG2 inhibitor in H1650, intrinsic EGFR-TKI resistant NSCLC cell harboring EGFR sensitive mutation, reversed EGFR-TKI resistance via I kappa B alpha restoration. Moreover, combination treatment of TG2 inhibitor and EGFR-TKI decreased the tumor growth in mouse xenograft models of EGFR mutant NSCLCs. Therefore, we have demonstrated that TG2 elicits the intrinsic EGFR-TKI resistance via PTEN loss and activation of NF-kappa B pathway. These results suggest that TG2 may be a useful predictive marker and also be a target for overcoming the resistance.