Repression of AXL expression by AP-1/JNK blockage overcomes resistance to PI3Ka therapy

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• AXL overexpression is a key resistance mechanism to anti-cancer drugs like BYL719 (Alpelisib), a PI3K inhibitor, in esophagus and head and neck squamous cell carcinoma (ESCC, HNSCC).
• The specific mechanisms driving AXL overexpression in response to BYL719 therapy remain unclear.

Purpose of the Study:

• To elucidate the mechanisms of AXL overexpression in BYL719 resistance in ESCC and HNSCC.
• To investigate the therapeutic potential of targeting AP-1 transcription factors and JNK signaling in combination with BYL719.

Main Methods:

• Correlation analysis of AXL and c-JUN expression in patient samples and cell lines.
• In vitro studies involving silencing of c-JUN and c-FOS, and combination treatment with BYL719 and SP600125 (JNK inhibitor).
• In vivo studies using xenograft and syngeneic models to evaluate combination therapy efficacy.

Main Results:

• c-JUN and c-FOS were identified as regulators of AXL overexpression in HNSCC and ESCC.
• Silencing c-JUN/c-FOS reduced AXL expression and sensitized tumor cells to BYL719.
• Combination of BYL719 and SP600125 demonstrated synergistic anti-proliferative effects, AXL downregulation, and mTOR pathway inhibition.
• In vivo studies confirmed tumor growth arrest with the BYL719-SP600125 combination.

Conclusions:

• JNK inhibition combined with anti-PI3K therapy represents a novel therapeutic strategy for ESCC and HNSCC.
• This combination therapy warrants clinical investigation in both HPV-positive and HPV-negative HNSCC and ESCC patients.