Supplementary Figure S7. Pathway to Pten/ Trp53 deficient prostate metastasis and therapy resistance. from MYC Drives Pten/Trp53-Deficient Proliferation and Metastasis due to IL6 Secretion and AKT Suppression via PHLPP2

Supplementary Figure S7. Pathway to Pten/ Trp53 deficient prostate metastasis and therapy resistance. Pten-loss triggers PIP3 signaling to activate AKT, which prompts activation of the p53/ p21/ p16 tumor suppressors and senescence arrest. Suppression and loss of p53 in this context results in cell proliferation and Il6 secretion. Il6 signals both auto and paracrine to activate Myc via the Jak/Stat pathway. Myc induces the Phlpp2 phosphatase which creates a negative feedback loop by dampening Akt activation. Metastases (and castration-resistant tumors) select for increased Myc expression (and gene amplification, and Akt inactivation, demonstrating that Myc supersedes the need for Akt in lethal prostate cancer.