AXL overexpression is a common resistance mechanism to anticancer therapies, including the resistance to BYL719 (Alpelisib) - the p110α isoform specific inhibitor of phosphoinositide 3-kinase (PI3K) - in esophagus squamous cell carcinoma (ESCC) and head and neck squamous cell carcinoma (HNSCC). However, the mechanisms underlying AXL overexpression in resistance to BYL719 remain elusive. Here, we demonstrate that the AP-1 transcription factors c-JUN and c-FOS regulate AXL overexpression in HNSCC and ESCC. The expression of AXL was correlated with that of c-JUN both in HNSCC patients and in HNSCC and ESCC cell lines. Silencing of c-JUN and c-FOS expression in tumor cells downregulated AXL expression and enhanced the sensitivity of human papilloma virus-positive (HPVPos) and -negative (HPVNeg) tumor cells to BYL719 in vitro. Blocking of JNK using SP600125 in combination with BYL719 showed a synergistic antiproliferative effect in vitro, which was accompanied by AXL downregulation and potent inhibition of the mTOR pathway. In vivo, the BYL719-SP600125 drug combination led to the arrest of tumor growth in cell line- derived and patient-derived xenograft models, as well as in syngeneic head and neck murine cancer models. Collectively, our data suggest that JNK inhibition, in combination with anti-PI3K therapy, is a new therapeutic strategy that should be tested in HPVPos and HPVNeg HNSCC and ESCC patients.