TY - JOUR
T1 - HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors
AU - Wang, Shizhen Emily
AU - Narasanna, Archana
AU - Perez-Torres, Marianela
AU - Xiang, Bin
AU - Wu, Frederick Y.
AU - Yang, Seungchan
AU - Carpenter, Graham
AU - Gazdar, Adi F.
AU - Muthuswamy, Senthil K.
AU - Arteaga, Carlos L.
N1 - Funding Information:
This work was supported by NCI R01 CA62212 (C.L.A.), R01 CA80195 (C.L.A.), Breast Cancer Specialized Program of Research Excellence (SPORE) grant P50 CA98131, Lung Cancer SPORE grant P50 CA90949, and Vanderbilt-Ingram Comprehensive Cancer Center Support Grant P30 CA68485. M.P.-T. is supported by NCI T32 CA78136.
PY - 2006/7
Y1 - 2006/7
N2 - HER2/Neu gene mutations have been identified in lung cancer. Expression of a HER2 mutant containing a G776YVMA insertion in exon 20 was more potent than wild-type HER2 in associating with and activating signal transducers, phosphorylating EGFR, and inducing survival, invasiveness, and tumorigenicity. HER2YVMA transphosphorylated kinase-dead EGFRK721R and EGFRWT in the presence of EGFR tyrosine kinase inhibitors (TKIs). Knockdown of mutant HER2 in H1781 lung cancer cells increased apoptosis and restored sensitivity to EGFR TKIs. The HER2 inhibitors lapatinib, trastuzumab, and CI-1033 inhibited growth of H1781 cells and cells expressing exogenous HER2YVMA. These data suggest that (1) HER2YVMA activates cellular substrates more potently than HER2WT; and (2) cancer cells expressing this mutation remain sensitive to HER2-targeted therapies but insensitive to EGFR TKIs.
AB - HER2/Neu gene mutations have been identified in lung cancer. Expression of a HER2 mutant containing a G776YVMA insertion in exon 20 was more potent than wild-type HER2 in associating with and activating signal transducers, phosphorylating EGFR, and inducing survival, invasiveness, and tumorigenicity. HER2YVMA transphosphorylated kinase-dead EGFRK721R and EGFRWT in the presence of EGFR tyrosine kinase inhibitors (TKIs). Knockdown of mutant HER2 in H1781 lung cancer cells increased apoptosis and restored sensitivity to EGFR TKIs. The HER2 inhibitors lapatinib, trastuzumab, and CI-1033 inhibited growth of H1781 cells and cells expressing exogenous HER2YVMA. These data suggest that (1) HER2YVMA activates cellular substrates more potently than HER2WT; and (2) cancer cells expressing this mutation remain sensitive to HER2-targeted therapies but insensitive to EGFR TKIs.
KW - SIGNALING
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U2 - 10.1016/j.ccr.2006.05.023
DO - 10.1016/j.ccr.2006.05.023
M3 - Article
C2 - 16843263
AN - SCOPUS:33745727112
SN - 1535-6108
VL - 10
SP - 25
EP - 38
JO - Cancer Cell
JF - Cancer Cell
IS - 1
ER -