Identification of a novel HER3 activating mutation homologous to EGFR-L858R in lung cancer.

[en] Somatic mutations found within the tyrosine kinase domain (TKD) of the human epidermal growth factor (HER) family of receptors have been implicated in the development and progression of non-small cell lung cancer (NSCLC). However, no conclusive reports have described pathogenic mutations in kinase-impaired HER3. Here, we report a case of an advanced chemotherapy-resistant NSCLC, harboring a novel HER3V855A somatic mutation homologous to the EGFRL858Ractivating mutation. Co-expression of HER3V855A and wild-type HER2 enhances ligand-induced transformation of murine and human cell lines, while HER-targeted inhibitors potently suppress mutant HER3 activity. Consistent with these observations, in silico computational modeling predicts that mutant V855A alters the kinase domain and c-terminal end of the HER3 protein. Taken together, these findings provide a basis for the clinical exploration of targeted therapies in HER3 mutant NSCLC and by extrapolation, in other cancers that more frequently carry somatic HER3 mutations.

Disciplines :

Oncology

Author, co-author :

Umelo, Ijeoma ; Université de Liège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases

Noeparast, Amir

Chen, Gang

Renard, Marleen

Geers, Caroline

Vansteenkiste, Johan

Giron, Philippe

De Wever, Olivier

Teugels, Erik

De Greve, Jacques

Language :

English

Title :

Identification of a novel HER3 activating mutation homologous to EGFR-L858R in lung cancer.

Publication date :

January 2016

Journal title :

Oncotarget

eISSN :

1949-2553

Publisher :

Impact Journals, United States - New York

Volume :

Issue :

Pages :

3068-83

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 06 June 2016

Statistics

Number of views

101 (2 by ULiège)

Number of downloads

148 (0 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

OpenAlex citations

Bibliography

Sharma, S.V. and J. Settleman, ErbBs in lung cancer. Exp Cell Res, 2009. 315: p. 557-71.
Pao, W. and N. Girard, New driver mutations in non-small-cell lung cancer. Lancet Oncol, 2011. 12: p. 175-80.
Soung, Y.H., et al., Somatic mutations of the ERBB4 kinase domain in human cancers. Int J Cancer, 2006. 118: p. 1426-9.
Wang, S.E., et al.,-HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell, 2006. 10: p. 25-38.
Soria, J.C., et al., EGFR-mutated oncogene-addicted non-small cell lung cancer: current trends and future prospects. Cancer Treat Rev, 2012. 38: p. 416-30.
Mok, T.S., et al., Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med, 2009. 361: p. 947-57.
Fukuoka, M., et al., Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol, 2011. 29: p. 2866-74.
Rosell, R., et al., Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol, 2012. 13: p. 239-46.
Solca, F., et al., Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther, 2012. 343: p. 342-50.
Li, D., et al., BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene, 2008. 27: p. 4702-11.
De Greve, J., et al., Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu. Lung Cancer, 2012. 76: p. 123-7.
Tvorogov, D., et al., Somatic mutations of ErbB4: selective loss-of-function phenotype affecting signal transduction pathways in cancer. J Biol Chem, 2009. 284: p. 5582-91.
Das, P.M., et al., Reactivation of epigenetically silenced HER4/ERBB4 results in apoptosis of breast tumor cells. Oncogene, 2010. 29: p. 5214-9.
TCGA, C.G.A.N., Comprehensive molecular characterization of human colon and rectal cancer. Nature, 2012. 487: p. 330-337.
TCGA, C.G.A.R.N., Diverse somatic mutation patterns and pathway alterations in human cancers. Nature, 2010. 466: p. 869-873.
Jeong, E.G., et al., ERBB3 kinase domain mutations are rare in lung, breast and colon carcinomas. Int J Cancer, 2006. 119: p. 2986-7.
Baselga, J. and S.M. Swain, Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer, 2009. 9: p. 463-75.
Campbell, M.R., D. Amin, and M.M. Moasser, HER3 comes of age: new insights into its functions and role in signaling, tumor biology, and cancer therapy. Clin Cancer Res, 2010. 16: p. 1373-83.
Sithanandam, G. and L.M. Anderson, The ERBB3 receptor in cancer and cancer gene therapy. Cancer Gene Ther, 2008. 15: p. 413-48.
Shi, F., et al., ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation. Proc Natl Acad Sci U S A, 2010. 107: p. 7692-7.
Feroz, K., E. Williams, and D.J. Riese, 2nd, ErbB2 and ErbB3 do not quantitatively modulate ligand-induced ErbB4 tyrosine phosphorylation. Cell Signal, 2002. 14: p. 793-8.
Berger, M.B., J.M. Mendrola, and M.A. Lemmon, ErbB3/HER3 does not homodimerize upon neuregulin binding at the cell surface. FEBS Lett, 2004. 569: p. 332-6.
Yarden, Y. and M.X. Sliwkowski, Untangling the ErbB signalling network. Nat Rev Mol Cell Biol, 2001. 2: p. 127-37.
Gullick, W.J., The c-erbB3/HER3 receptor in human cancer. Cancer Surv, 1996. 27: p. 339-49.
Amin, D.N., M.R. Campbell, and M.M. Moasser, The role of HER3, the unpretentious member of the HER family, in cancer biology and cancer therapeutics. Semin Cell Dev Biol, 2010. 21: p. 944-50.
Hsieh, A.C. and M.M. Moasser, Targeting HER proteins in cancer therapy and the role of the non-target HER3. Br J Cancer, 2007. 97: p. 453-7.
Gazdar, A.F., Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene, 2009. 28 Suppl 1: p. S24-31.
De Greve, J., et al., Prospective evalutaiton of first-line tyrosine kinase inhibition with erlotinib in patients with advanced non-small cell lung cancer (NSCLC) harbouring a mutant EGFR gene (FIELT study): P3-079. Journal of Thoracic Oncology, 2007. 2: p. p S712.
Shahi, R.B., et al., Detection of EGFR-TK Domain-activating Mutations in NSCLC With Generic PCR-based Methods. Diagn Mol Pathol, 2014.
Huse, M. and J. Kuriyan, The conformational plasticity of protein kinases. Cell, 2002. 109: p. 275-82.
Pao, W., et al., EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A, 2004. 101: p. 13306-11.
Marks, J.L., et al., Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4. PLoS One, 2007. 2: p. e426.
Naoki, K., et al., Missense mutations of the BRAF gene in human lung adenocarcinoma. Cancer Res, 2002. 62: p. 7001-3.
Andreadi, C., et al., The intermediate-activity (L597V)BRAF mutant acts as an epistatic modifier of oncogenic RAS by enhancing signaling through the RAF/MEK/ERK pathway. Genes Dev, 2012. 26: p. 1945-58.
Riese, D.J., 2nd, et al., The cellular response to neuregulins is governed by complex interactions of the erbB receptor family. Mol Cell Biol, 1995. 15: p. 5770-6.
Gollamudi, M., et al., Autocrine activation of ErbB2/ErbB3 receptor complex by NRG-1 in non-small cell lung cancer cell lines. Lung Cancer, 2004. 43: p. 135-43.
Rusch, V., et al., Overexpression of the epidermal growth factor receptor and its ligand transforming growth factor alpha is frequent in resectable non-small cell lung cancer but does not predict tumor progression. Clin Cancer Res, 1997. 3: p. 515-22.
Schlessinger, J., Cell signaling by receptor tyrosine kinases. Cell, 2000. 103: p. 211-25.
Miller, V.A., et al., Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol, 2012. 13: p. 528-38.
Yang, J., et al., LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. Journal of Clinical Oncology Supplement, 2012. 30
Metzger-Filho, O., E.P. Winer, and I. Krop, Pertuzumab: optimizing HER2 blockade. Clin Cancer Res, 2013. 19: p. 5552-6.
Roy, A., A. Kucukural, and Y. Zhang, I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc, 2010. 5: p. 725-38.
Xu, D. and Y. Zhang, Improving the physical realism and structural accuracy of protein models by a two-step atomic-level energy minimization. Biophys J, 2011. 101: p. 2525-34.
Tanyalcin, I., et al., I-PV: a CIRCOS module for interactive protein sequence visualization. Bioinformatics, 2015.
Jaiswal, B.S., et al., Oncogenic ERBB3 mutations in human cancers. Cancer Cell, 2013. 23: p. 603-17.
Ferrer-Costa, C., M. Orozco, and X. de la Cruz, Characterization of disease-associated single amino acid polymorphisms in terms of sequence and structure properties. J Mol Biol, 2002. 315: p. 771-86.
Jiang, J., et al., Epidermal growth factor-independent transformation of Ba/F3 cells with cancer-derived epidermal growth factor receptor mutants induces gefitinib-sensitive cell cycle progression. Cancer Res, 2005. 65: p. 8968-74.
Littlefield, P., et al., Structural analysis of the EGFR/HER3 heterodimer reveals the molecular basis for activating HER3 mutations. Sci Signal, 2014. 7: p. ra114.
Shigematsu, H., et al., Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res, 2005. 65: p. 1642-6.
Lahiri, S.D., et al., The pentacovalent phosphorus intermediate of a phosphoryl transfer reaction. Science, 2003. 299: p. 2067-71.
Agus, D.B., et al., Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell, 2002. 2: p. 127-37.
Junttila, T.T., et al., Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell, 2009. 15: p. 429-40.
De Brakeleer, S., et al., Cancer predisposing missense and protein truncating BARD1 mutations in non-BRCA1 or BRCA2 breast cancer families. Hum Mutat, 2010. 31: p. E1175-85.
Trulzsch, B., et al., DGGE is more sensitive for the detection of somatic point mutations than direct sequencing. Biotechniques, 1999. 27: p. 266-8.
Pedersen, N.M., et al., Expression of epidermal growth factor receptor or ErbB3 facilitates geldanamycin-induced down-regulation of ErbB2. Mol Cancer Res, 2009. 7: p. 275-84.
Tao, R.H. and I.N. Maruyama, All EGF(ErbB) receptors have preformed homo-and heterodimeric structures in living cells. J Cell Sci, 2008. 121: p. 3207-17.
Offterdinger, M. and P.I. Bastiaens, Prolonged EGFR signaling by ERBB2-mediated sequestration at the plasma membrane. Traffic, 2008. 9: p. 147-55.
Kaplan, W. and T.G. Littlejohn, Swiss-PDB Viewer (Deep View). Brief Bioinform, 2001. 2: p. 195-7.
Harris, M. and T.A. Jones, Molray-a web interface between O and the POV-Ray ray tracer. Acta Crystallogr D Biol Crystallogr, 2001. 57: p. 1201-3.