Reference Detail

Ref Type Journal Article
PMID (22908275)
Authors Greulich H, Kaplan B, Mertins P, Chen TH, Tanaka KE, Yun CH, Zhang X, Lee SH, Cho J, Ambrogio L, Liao R, Imielinski M, Banerji S, Berger AH, Lawrence MS, Zhang J, Pho NH, Walker SR, Winckler W, Getz G, Frank D, Hahn WC, Eck MJ, Mani DR, Jaffe JD, Carr SA, Wong KK, Meyerson M
Title Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2.
Journal Proceedings of the National Academy of Sciences of the United States of America
Vol 109
Issue 36
Date 2012 Sep 4
URL
Abstract Text We assessed somatic alleles of six receptor tyrosine kinase genes mutated in lung adenocarcinoma for oncogenic activity. Five of these genes failed to score in transformation assays; however, novel recurring extracellular domain mutations of the receptor tyrosine kinase gene ERBB2 were potently oncogenic. These ERBB2 extracellular domain mutants were activated by two distinct mechanisms, characterized by elevated C-terminal tail phosphorylation or by covalent dimerization mediated by intermolecular disulfide bond formation. These distinct mechanisms of receptor activation converged upon tyrosine phosphorylation of cellular proteins, impacting cell motility. Survival of Ba/F3 cells transformed to IL-3 independence by the ERBB2 extracellular domain mutants was abrogated by treatment with small-molecule inhibitors of ERBB2, raising the possibility that patients harboring such mutations could benefit from ERBB2-directed therapy.

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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
Variant Impact Protein Effect Variant Description Associated with drug Resistance
C311R missense gain of function ERBB2 (HER2) C311R lies within the extracellular domain of the Erbb2 (Her2) protein (PMID: 22908275). C311R results in disulfide bond-mediated Erbb2 (Her2) dimerization and is transforming in cell culture (PMID: 22908275).
C334S missense gain of function ERBB2 (HER2) C334S lies within the extracellular domain of the Erbb2 (Her2) protein (PMID: 22908275). C334S results in disulfide bond-mediated Erbb2 (Her2) dimerization and is transforming in cell culture (PMID: 22908275).
D326G missense no effect ERBB2 (HER2) D326G lies within the extracellular domain of the Erbb2 (Her2) protein (PMID: 22908275). D326G does not result in increased Erbb2 (Her2) phosphorylation or the ability to transform cells in culture (PMID: 22908275).
D845A missense loss of function ERBB2 (HER2) D845A lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). D845A results in loss of Erbb2 (Her2) phosphorylation and abolishes transformation potential in cell culture (PMID: 22908275).
E321G missense gain of function ERBB2 (HER2) E321G lies within the extracellular domain of the Erbb2 (Her2) protein (PMID: 22908275). E321G results in disulfide bond-mediated Erbb2 (Her2) dimerization and is transforming in cell culture (PMID: 22908275, PMID: 29533785).
G309E missense unknown ERBB2 (HER2) G309E lies within the extracellular domain of the Erbb2 (Her2) protein (PMID: 22908275). G309E results in disulfide bond-mediated Erbb2 (Her2) dimerization and is transforming in cell culture (PMID: 22908275), but in another study, G309E results in similar cell proliferation and viability levels as wild-type Erbb2 (Her2), in two different cell lines (PMID: 29533785).
L49H missense no effect ERBB2 (HER2) L49H lies within the extracellular domain of the Erbb2 (Her2) protein (PMID: 22908275). L49H demonstrates phosphorylation level and transformation potential comparable to wild-type Erbb2 (Her2) protein in cell culture (PMID: 22908275).
N319D missense no effect ERBB2 (HER2) N319D lies within the extracellular domain of the Erbb2 (Her2) protein (PMID: 22908275). N319D demonstrates phosphorylation level and transformation potential comparable to wild-type Erbb2 (Her2) protein in cell culture (PMID: 22908275).
R432W missense unknown ERBB2 (HER2) R432W lies within the extracellular domain of the Erbb2 (Her2) protein (PMID: 22908275). R432W has not been characterized in the scientific literature and therefore, its effect on Erbb2 (Her2) protein function is unknown (PubMed, Apr 2019).
S310F missense gain of function ERBB2 (HER2) S310F lies within the extracellular domain of the Erbb2 (Her2) protein (PMID: 22908275). S310F confers a gain of function to Erbb2 (Her2) as indicated by increased phosphorylation of Erbb2 (Her2) and downstream signaling, colony formation, migration, transformation in cell culture (PMID: 22908275, PMID: 29533785, PMID: 29967253, PMID: 29954840), and enhanced tumor growth in mouse models (PMID: 29954840).
S310Y missense gain of function ERBB2 (HER2) S310Y lies within the extracellular domain of the Erbb2 (Her2) protein (PMID: 22908275). S310Y confers a gain of function to Erbb2 (Her2) as indicated by increased downstream p-AKT and p-ERK signaling, colony formation, migration, and transformation potential in cell culture (PMID: 22908275, PMID: 29967253; PMID: 29954840), increased cell proliferation and cell viability as compared to wild-type Erbb2 (Her2) in one of two cell lines (PMID: 29533785), and enhanced tumor growth in mouse models (PMID: 29954840).
T216S missense gain of function - predicted ERBB2 (HER2) T216S lies within the extracellular domain of the Erbb2 (Her2) protein (PMID: 22908275). T216S is predicted to confer a gain of function to the Erbb2 (Her2) protein as demonstrated by increased kinase activity (PMID: 22908275).
V750E missense loss of function - predicted ERBB2 (HER2) V750E lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). V750E is predicted to confer a loss of function to the Erbb2 (Her2) protein as demonstrated by decreased kinase activity (PMID: 22908275).
V777A missense loss of function ERBB2 (HER2) V777A lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). V777A results in decreased Erbb2 (Her2) activity and a decreased ability to transform cells in culture (PMID: 22908275).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 S310F Advanced Solid Tumor sensitive Neratinib Preclinical Actionable In a preclinical study, Nerlynx (neratinib) decreased cell survival of transformed human cells expressing ERBB2 (HER2) S310F (PMID: 22908275). 22908275
ERBB2 S310F Advanced Solid Tumor sensitive Lapatinib Preclinical Actionable In a preclinical study, Tykerb (lapatinib) inhibited proliferation of transformed cells expressing ERBB2 S310F in culture (PMID: 22908275). 22908275