Figure 7. Proposed mechanism of AP-1/AXL–driven resistance to PI3Kαi in HNSCC and ESCC.
In BYL719-resistant HNSCC and ESCC cell lines, overexpressed AXL dimerizes with EGFR and activates mTOR signaling in an AKT-independent manner. Upregulation of AXL is mediated by the AP-1 transcription factors c-JUN and c-FOS and induces EGFR phosphorylation (yellow star). Blocking c-JUN with the JNK inhibitor SP600125 reduces AXL expression and, hence, sensitizes the tumor cells to BYL719 via preventing mTOR pathway activation.