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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.

cancer science

Amphiregulin 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