PTEN and nonpapillary renal cell carcinoma: Downregulation of OTUD1 can lead to VEGFR-TKI resistance in clear cell renal carcinoma (ccRCC) via the OTUD1-PTEN axis.131 Glutaminase 2 (GT2) is also a posttranslational modifying enzyme that induces PTEN degradation, and its high expression is associated with resistance to erlotinib and gefitinib in NSCLC cell lines.132 Retinol-binding protein 2 (RBP2) is a histone demethylase that directly downregulates PTEN expression.