期刊
ONCOTARGET
卷 7, 期 17, 页码 23300-23311出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.8188
关键词
head and neck cancer; MAPK1; ERK2; mutation; amphiregulin
资金
- National Cancer Institute Head and Neck Cancer SPORE [P50 CA097190]
- National Cancer Institute [K07 CA137140]
- Sun Yat-Sen University [5010 Plan 2010004]
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have not been effective in unselected head and neck squamous cell carcinoma (HNSCC) populations. We previously reported an exceptional response to a brief course of erlotinib in a patient with advanced HNSCC whose tumor harbored a MAPK1(E322K) somatic mutation. MAPK1(E322K) was associated with increased p-EGFR, increased EGFR downstream signaling and increased sensitivity to erlotinib. In this study, we investigated the mechanism of MAPK1(E322K)-mediated EGFR activation in the context of erlotinib sensitivity. We demonstrated increased AREG secretion in HNSCC cell lines harboring endogenous or exogenous MAPK1(E322K) compared to wild type MAPK1. We found inhibition or knockdown of MAPK1 with siRNA resulted in reduced secretion of AREG and decreased sensitivity to erlotinib in the setting of MAPK1(E322K). MAPK1(E322K) was associated with increased AREG secretion leading to an autocrine feedback loop involving AREG, EGFR and downstream signaling. Knockdown of AREG in HNSCC cells harboring MAPK1(E322K) abrogated EGFR signaling and decreased sensitivity to erlotinib in vitro and in vivo. These cumulative findings implicate increased AREG secretion and EGFR activation as contributing to increased erlotinib sensitivity in MAPK1(E322K) HNSCC.
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