|Title||SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer.|
|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||Mu P, Zhang Z, Benelli M, Karthaus WR, Hoover E, Chen C-C, Wongvipat J, Ku S-Y, Gao D, Cao Z, Shah N, Adams EJ, Abida W, Watson PA, Prandi D, Huang C-H, de Stanchina E, Lowe SW, Ellis L, Beltran H, Rubin MA, Goodrich DW, Demichelis F, Sawyers CL|
|Date Published||2017 Jan 06|
Some cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the drug target. We use in vitro and in vivo human prostate cancer models to show that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR)-dependent luminal epithelial cells to AR-independent basal-like cells. This lineage plasticity is enabled by the loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2, and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching.
|Grant List||P01 CA013106 / CA / NCI NIH HHS / United States |
P30 CA008748 / CA / NCI NIH HHS / United States