AXL overexpression is a common resistance mechanism to anti-cancer therapies, including the p110 isoform specific inhibitor of the phosphoinositide 3-kinase (PI3K), BYL719, in esophagus and head and neck squamous cell carcinoma (ESCC, HNSCC respectively). However, the mechanisms underlying AXL overexpression in resistance to BYL719 remained elusive. Here we demonstrated that the AP-1 transcription factors, c-JUN and c-FOS, regulates AXL overexpression in HNSCC and ESCC. AXL and c-JUN expression is correlated in HNSCC patients, and in HNSCC and ESCC cell lines. Silencing of c-JUN and c-FOS expression in tumor cells reduced AXL expression, and enhanced sensitivity of human papilloma virus positive (HPV Pos ) and negative (HPV Neg ) tumor cells to BYL719 in vitro. Blocking of the c-JUN N-terminal kinase (JNK), using SP600125, in combination with BYL719 resulted in down-regulation of AXL expression, and potently inhibited mTOR pathway. Synergistic anti-proliferative effect was detected between BYL719 and SP600125 in 15 tumor cell lines in vitro. In-vivo, this drug combination induced tumor growth arrest in cell line and patients-derived xenograft models, and in syngeneic head and neck cancer models. Collectively, our data suggests that JNK inhibition in combination with anti-PI3K therapy is a new therapeutic strategy that may be tested in HPV Pos and HPV Neg HNSCC and ESCC patients.