No abstract

An understanding of the mechanisms underlying acquired resistance to cetuximab is urgently needed to improve cetuximab efficacy in patients with head and neck squamous cell carcinoma (HNSCC). Here, we present a clinical observation that MET pathway activation constitutes the mechanism of acquired resistance to cetuximab in a patient with HNSCC. Specifically, RNA sequencing and mass spectrometry analysis of cetuximab‐sensitive (CetuxSen) and cetuximab‐resistant (CetuxRes) tumors indicated MET amplification and overexpression in the CetuxRes tumor compared to the CetuxSen lesion. Stimulation of MET in HNSCC cell lines was sufficient to reactivate the MAPK pathway and to confer resistance to cetuximab in vitro and in vivo. In addition to the direct role of MET in reactivation of the MAPK pathway, MET stimulation abrogates the well‐known cetuximab‐induced compensatory feedback loop of HER2/HER3 expression. Mechanistically, we showed that the overexpression of HER2 and HER3 following cetuximab treatment is mediated by the ETS homologous transcription factor (EHF), and is suppressed by MET/MAPK pathway activation. Collectively, our findings indicate that evaluation of MET and HER2/HER3 in response to cetuximab in HNSCC patients can provide the rationale of successive line of treatment.

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.