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Two growth pathways in prostate cancer prop each other up: block one and the other switches on, which is why single drugs fail and the pair has to be blocked together.
Androgen receptor transcriptional output is decreased in human and murine prostate tumours with PTEN deletion, and PI3K pathway inhibition activates androgen receptor signalling by relieving feedback inhibition of the HER kinases. Conversely, androgen receptor inhibition activates AKT signalling by reducing levels of the AKT phosphatase PHLPP. The two oncogenic pathways therefore cross-regulate each other by reciprocal feedback, and inhibiting one activates the other, maintaining tumour cell survival. Combined pharmacological inhibition of PI3K and androgen receptor signalling caused near-complete prostate cancer regressions in a Pten-deficient murine prostate cancer model and in human prostate cancer xenografts.
It is the reason every prostate PI3K or AKT trial gives the drug with abiraterone rather than alone, and the reason PTEN loss is used to select for those combinations rather than as a general prognostic marker.
Shares PTEN alteration (sequencing) and PTEN loss (IHC), PTEN, AKT, Androgen receptor signalling.
Shares PTEN alteration (sequencing) and PTEN loss (IHC), PTEN, AKT, Androgen receptor signalling.
Shares Cancer Cell, Androgen receptor signalling, Resistance routes: how a blocked pathway comes back, Castration-resistant prostate cancer (CRPC).
Shares Androgen receptor signalling, Resistance routes: how a blocked pathway comes back, Castration-resistant prostate cancer (CRPC), Drug resistance (primary and acquired).
Shares Androgen receptor signalling, Resistance routes: how a blocked pathway comes back, Castration-resistant prostate cancer (CRPC), Drug resistance (primary and acquired).
Shares Androgen receptor signalling, Castration-resistant prostate cancer (CRPC), Drug resistance (primary and acquired), Androgen receptor.
Shares PTEN alteration (sequencing) and PTEN loss (IHC), PTEN, AKT, PIK3CA / PI3K-alpha.
Shares Androgen receptor signalling, Castration-resistant prostate cancer (CRPC), Drug resistance (primary and acquired), Androgen receptor.