Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2.
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.
Department of Medical Oncology, Center for Cancer Genome Discovery, and Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. heidig@broadinstitute.org
Heidi
H
Greulich
Bethany
B
Kaplan
Philipp
P
Mertins
Tzu-Hsiu
TH
Chen
Kumiko E
KE
Tanaka
Cai-Hong
CH
Yun
Xiaohong
X
Zhang
Se-Hoon
SH
Lee
Jeonghee
J
Cho
Lauren
L
Ambrogio
Rachel
R
Liao
Marcin
M
Imielinski
Shantanu
S
Banerji
Alice H
AH
Berger
Michael S
MS
Lawrence
Jinghui
J
Zhang
Nam H
NH
Pho
Sarah R
SR
Walker
Wendy
W
Winckler
Gad
G
Getz
David
D
Frank
William C
WC
Hahn
Michael J
MJ
Eck
D R
DR
Mani
Jacob D
JD
Jaffe
Steven A
SA
Carr
Kwok-Kin
KK
Wong
Matthew
M
Meyerson
D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics; D000077192:Adenocarcinoma of Lung; D000483:Alleles; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D019281:Dimerization; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D009154:Mutation / Q000235:genetics*; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D017434:Protein Structure, Tertiary / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D012190:Retroviridae; D053719:Tandem Mass Spectrometry
D017931:DNA Primers; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human