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|Ref Type||Journal Article|
|Authors||Hong YS, Kim J, Pectasides E, Fox C, Hong SW, Ma Q, Wong GS, Peng S, Stachler MD, Thorner AR, Van Hummelen P, Bass AJ|
|Title||Src mutation induces acquired lapatinib resistance in ERBB2-amplified human gastroesophageal adenocarcinoma models.|
|Abstract Text||ERBB2-directed therapy is now a routine component of therapy for ERBB2-amplified metastatic gastroesophageal adenocarcinomas. However, there is little knowledge of the mechanisms by which these tumors develop acquired resistance to ERBB2 inhibition. To investigate this question we sought to characterize cell line models of ERBB2-amplified gastroesophageal adenocarcinoma with acquired resistance to ERBB2 inhibition. We generated lapatinib-resistant (LR) subclones from an initially lapatinib-sensitive ERBB2-amplified esophageal adenocarcinoma cell line, OE19. We subsequently performed genomic characterization and functional analyses of resistant subclones with acquired lapatinib resistance. We identified a novel, acquired SrcE527K mutation in a subset of LR OE19 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 OE19 cells. Ectopic expression of SrcE527K 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 ERBB2 inhibition in ERBB2-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 ERBB2 inhibition in esophageal and gastric adenocarcinoma.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|SRC||E527K||missense||gain of function||SRC E527K does not lie within any known functional domains of the Src protein (UniProt.org). E527K results in resistance of Src to phosphorylation and inactivation by CSK, increased Src kinase activity and phosphorylation in culture, leading to blood and bone pathologies in animal models (PMID: 7592628, PMID: 26936507), and is associated with drug resistance in culture (PMID: 25350844).||Y|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|ERBB2 amp SRC E527K||gastroesophageal junction adenocarcinoma||sensitive||Lapatinib + Saracatinib||Preclinical - Cell culture||Actionable||In a preclinical study, the combination of Tykerb (lapatinib) and Saracatinib (AZD0530) inhibited growth of ERBB2 (HER2)-amplified gastroesophageal adenocarcinoma cells harboring SRC E527K in culture (PMID: 25350844).||25350844|
|ERBB2 amp SRC E527K||gastroesophageal junction adenocarcinoma||resistant||Lapatinib||Preclinical - Cell culture||Actionable||In a preclinical study, an ERBB2 (HER2)-amplified gastroesophageal cancer cell line initially sensitive to treatment with Tykerb (lapatinib) in culture developed resistance and was subsequently found to have acquired a secondary drug resistant mutation, SRC E527K (PMID: 25350844).||25350844|