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Figure 4. Selective adaptive resistance mechanisms in response to PI3K pathway inhibition. A: A PTEN/Src/p130Cas signalling axis activates CRKL/p110β in PTEN-deficient tumour cells, providing a link between PTEN loss and activation of p110β in these cells (left). Specific PI3Kβ inhibition cause feedback upregulation of IRS1 and IGF1R which then activates the PI3Kα isoform and results in a rebound of PI3K signalling following transient suppression (right). The androgen receptor downstream of several RTKs also provides another escape mechanism for continued survival following PI3K inhibition; B: similar to MEK inhibition, PI3K inhibition also reprograms the transcriptional machinery controlled by BRD4, leading to induced upregulation of multiple RTKs and MYC; C: a ubiquitin-based mechanism of adaptive resistance to PI3K inhibition mediated by the E3 ubiquitin ligase Skp2. PI3K inhibition leads to increased Skp2 expression and activity, which ubiquitinates and enhances the activation of AKT