Open AccessAmphiregulin triggered epidermal growth factor receptor activation confers in vivo crizotinib‐resistance of EML 4‐ ALK lung cancer and circumvention by epidermal growth factor receptor inhibitors
Author(s) -
Taniguchi Hirokazu,
Takeuchi Shinji,
Fukuda Koji,
Nakagawa Takayuki,
Arai Sachiko,
Nanjo Shigeki,
Yamada Tadaaki,
Yamaguchi Hiroyuki,
Mukae Hiroshi,
Yano Seiji
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13111
Subject(s) - crizotinib , amphiregulin , epidermal growth factor receptor , cancer research , erlotinib , cetuximab , gefitinib , anaplastic lymphoma kinase , alectinib , lung cancer , epidermal growth factor , biology , erlotinib hydrochloride , medicine , cancer , immunology , receptor , monoclonal antibody , antibody , malignant pleural effusion
Crizotinib, a first‐generation anaplastic lymphoma kinase ( ALK ) tyrosine‐kinase inhibitor, is known to be effective against echinoderm microtubule‐associated protein‐like 4 ( EML 4 )‐ ALK ‐positive non‐small cell lung cancers. Nonetheless, the tumors subsequently become resistant to crizotinib and recur in almost every case. The mechanism of the acquired resistance needs to be deciphered. In this study, we established crizotinib‐resistant cells (A925 LPE 3‐ CR ) via long‐term administration of crizotinib to a mouse model of pleural carcinomatous effusions; this model involved implantation of the A925 LPE 3 cell line, which harbors the EML 4‐ ALK gene rearrangement. The resistant cells did not have the secondary ALK mutations frequently occurring in crizotinib‐resistant cells, and these cells were cross‐resistant to alectinib and ceritinib as well. In cell clone #2, which is one of the clones of A925 LPE 3‐ CR , crizotinib sensitivity was restored via the inhibition of epidermal growth factor receptor ( EGFR ) by means of an EGFR tyrosine‐kinase inhibitor (erlotinib) or an anti‐ EGFR antibody (cetuximab) in vitro and in the murine xenograft model. Cell clone #2 did not have an EGFR mutation, but the expression of amphiregulin ( AREG ), one of EGFR ligands, was significantly increased. A knockdown of AREG with small interfering RNA s restored the sensitivity to crizotinib. These data suggest that overexpression of EGFR ligands such as AREG can cause resistance to crizotinib, and that inhibition of EGFR signaling may be a promising strategy to overcome crizotinib resistance in EML 4‐ ALK lung cancer.