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 .

Diseases
Validation

Diseases presenting "cancer" symptom

achondroplasia

acute rheumatic fever

adrenal incidentaloma

alpha-thalassemia

benign recurrent intrahepatic cholestasis

cadasil

canavan disease

carcinoma of the gallbladder

cholangiocarcinoma

coats disease

congenital adrenal hyperplasia

congenital diaphragmatic hernia

cowden syndrome

cushing syndrome

cutaneous mastocytosis

dedifferentiated liposarcoma

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

familial hypocalciuric hypercalcemia

familial mediterranean fever

gm1 gangliosidosis

heparin-induced thrombocytopenia

hereditary cerebral hemorrhage with amyloidosis

hirschsprung disease

hodgkin lymphoma, classical

inclusion body myositis

junctional epidermolysis bullosa

kabuki syndrome

kallmann syndrome

kindler syndrome

lamellar ichthyosis

liposarcoma

locked-in syndrome

lymphangioleiomyomatosis

monosomy 21

neuralgic amyotrophy

oculocutaneous albinism

oligodontia

oral submucous fibrosis

papillon-lefèvre syndrome

pendred syndrome

pleomorphic liposarcoma

primary effusion lymphoma

proteus syndrome

pyomyositis

pyruvate dehydrogenase deficiency

severe combined immunodeficiency

sneddon syndrome

systemic capillary leak syndrome

triple a syndrome

von hippel-lindau disease

waldenström macroglobulinemia

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

This symptom has already been validated