Induced Proteasomal Degradation of TET2 Leads to EGFR-Tyrosine Kinase Inhibitor Resistance In NSCLC

Epidermal growth factor receptor (EGFR) mutations are noted in a significant number of Caucasian and East-Asian patients with non-small cell lung cancer (NSCLC). EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are effective therapies for many of these people, though acquired resistance (AR) to these agents is common. The molecular mechanisms underlying AR development have been documented in perhaps two-thirds of cases, but the events that cause AR in the remaining third of patients are unknown. Based on additional evidence, more attention is being focused on epigenetic alterations playing a role in AR, particularly DNA methylation perturbations.

New work by Zhang et al. investigated the connection between the family of ten-eleven translocation proteins (i.e., TET1, TET2, and TET3) and NSCLC EGFR-TKI resistance (1). The authors found that TET2, more than TET1 or TET3, was decreased in NSCLC cell lines resistant to the EGFR-TKI osimertinib, consistent with what they saw in clinical samples from patients with disease progression following osimertinib therapy. Subsequent TET2 knockdown, knockout and xenograft studies all underscored the importance of TET2 loss in EGFR-TKI resistance. A series of mechanistic experiments demonstrated that MEK1 enhances TET2 stabilization via Ser¹¹⁰⁷ phosphorylation while TET2 undergoes proteasomal degradation following CUL7/FBXW11-mediated polyubiquitination. The Ser¹¹⁰⁷ phosphorylation interferes with FBXW11 binding to TET2. TET2 loss due to MEK1 inhibition increased TNF/NF-κB signaling and evoked EGFR-TKI resistance. The researchers then showed that targeting NF-κB activity reduced TKI resistance in vitro and in vivo. In summary, Zhang et al. present a novel TET2-dependent pathway for EGFR-TKI resistance and indicate that targeting NF-κB signaling may be a way to thwart it.

GeneTex offers an extensive catalog of quality antibodies and reagents for epigenetics research, including the well-published TET1 antibody [GT1462] (GTX627420) and TET3 antibody [C3], C-term (GTX121453) cited in the Zhang et al. study. For more information, please see the product images below and visit www.genetex.com.