Src Mutation Induces Acquired Lapatinib Resistance in ERBB2-Amplified Human Gastroesophageal Adenocarcinoma Models.

[esophageal adenocarcinoma]

ERBB 2 -directed therapy is now a routine component of therapy for ERBB 2 -amplified metastatic gastroesophageal adenocarcinomas . However , there is little knowledge of the mechanisms by which these tumors develop acquired resistance to ERBB 2 inhibition . To investigate this question we sought to characterize cell line models of ERBB 2 -amplified gastroesophageal adenocarcinoma with acquired resistance to ERBB 2 inhibition . We generated lapatinib-resistant (LR ) subclones from an initially lapatinib-sensitive ERBB 2 -amplified esophageal adenocarcinoma cell line , OE 19 . We subsequently performed genomic characterization and functional analyses of resistant subclones with acquired lapatinib resistance . We identified a novel , acquired SrcE 527 K mutation in a subset of LR OE 19 subclones . Cells with this mutant allele harbour increased Src phosphorylation . Genetic and pharmacologic inhibition of Src resensitized these subclones to lapatinib . Biochemically , Src mutations could activate both the phosphatidylinositol 3 -kinase and mitogen activated protein kinase pathways in the lapatinib-treated LR OE 19 cells . Ectopic expression of Src E 527 K mutation also was sufficient to induce lapatinib resistance in drug-naïve cells . These results indicate that pathologic activation of Src is a potential mechanism of acquired resistance to ERBB 2 inhibition in ERBB 2 -amplified gastroesophageal cancer . Although Src mutation has not been described in primary tumor samples , we propose that the Src hyperactivation should be investigated in the settings of acquired resistance to ERBB 2 inhibition in esophageal and gastric adenocarcinoma .