Indicators that can guide clinical decisions in cancer, particularly posttranslational modification of proteins which result in altered prognosis and differential sensitivity to targeted cancer therapy, are provided. In particular, monitoring of phosphorylation of PTEN may be utilized to predict or assess drug response, drug sensitivity, and clinical outcome. Modulation of PTEN phosphorylation may be utilized to alter sensitivity and outcome in cancer patients. Posttranslational modification of PTEN, particularly phosphorylation, is correlated with resistance to targeted cancer therapy, including EGFR inhibitors, and with reduced survival prognosis. Methods and assays for determining phosphorylation of PTEN, particularly Y240 phosphorylation, are provided. Methods for sensitizing tumors to inhibition and targeted therapy by modulating PTEN phosphorylation are provided.
