Signaling by ERBB2 in Cancer

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Gene amplification of the ERBB2 (HER2) oncogene is observed across various different cancer types. In addition to HER2 gene amplification, sequencing of tumour samples have revealed HER2 mutations, which fall within three major regions: the extracellular domain (ECD), transmembrane domain/ juxtamembrane domain (TMD/JMD) and kinase domain (KD). Based on the functional studies of their catalytic activity, signaling and drug sensitivity, as well as their time of occurence with respect to treatment, these mutation can be classified as primary mutations, that can be activating or silent, and may confer drug resistance, and secondary mutations, associated with development of drug resistance upon initial response to targeted therapy.

Overexpression of ERBB2 (HER2) protein, usually as a consequence of ERBB2 gene amplification, leads to formation of constitutively active, growth factor independent, ERBB2 homodimers, which are sensitive to the therapeutic antibody trastuzumab (herceptin) (Pickl and Ries 2009).
Co-overexpression of ERBB2 and its dimerization partner ERBB3 leads to formation of both ERBB2 homodimers and ERRB2:ERBB3 heterodimers and is associated with chemotherapy resistance and reduced relapse-free and overall survival (Spears et al. 2012).

Mutations in the kinase domain (KD) of ERBB2 result in constitutive activation of ERBB2 signaling, facilitate heterodimerization of ERBB2 with other EGFR family members and increase the signaling intensity (Kancha et al. 2011). Functionally studied ERBB2 KD mutants include ERBB2 L755S, ERBB2 L755P, ERBB2 I767M, ERBB2 D769H, ERBB2 V777L, ERBB2 G778_P780dup, ERBB2 T798I, ERBB2 T798M, ERBB2 V842I, ERBB2 T862A, ERBB2 L869R, ERBB2 H878Y and ERBB2 R896C (Kancha et al. 2011, Bose et al. 2013, Collier et al. 2013, Hu, Wan et al. 2015; Hu, Hu et al. 2015, Hanker et al. 2017, Croessmann et al. 2019).

Sensitivity to tyrosine kinase inhibitors (TKIs) and the therapeutic antibody trastuzumab (herceptin) differs between different ERBB2 KD mutants (Bose et al. 2013, Rexer et al. 2013, Nagano et al. 2018).

ERBB2 extracellular domain (ECD) mutants harbor missense mutations that lead to substitutions of amino acid residues in the heterodimerization arm contact surface, involved in formation of ERBB2 heterodimers (Greulich et al. 2012).

Recurrent missense mutations in regions encoding the transmembrane domain (TMD) and the juxtamembrane domain (JMD) are frequently reported in cancer. TMD and JMD mutations can activate ERBB2 signaling by improving the active dimer interface or by stabilizing the active conformation (Ou et al. 2017, Pahuja et al. 2018).

ERBB2 TMD/JMD mutants differ in their sensitivity to the therapeutic antibody pertuzumab, which blocks ligand-driven heterodimerization of ERBB2 (Pahuja et al. 2018).

Literature References
PubMed ID Title Journal Year
30314968 Combined Blockade of Activating ERBB2 Mutations and ER Results in Synthetic Lethality of ER+/HER2 Mutant Breast Cancer

Formisano, L, Sudhan, DR, Arteaga, CL, Nagy, RJ, Croessmann, S, Kinch, LN, Bernicker, EH, Mathew, A, Gonzalez-Ericsson, PI, Grishin, NV, Lanman, RB, Cutler, RE, Lalani, AS, He, J, Miller, VA, Cristofanilli, M

Clin. Cancer Res. 2019
29967253 High-Throughput Functional Evaluation of Variants of Unknown Significance in ERBB2

Kojima, S, Ueno, T, Iwase, H, Nagano, M, Kohsaka, S, Mano, H, Saka, K, Kawazu, M

Clin. Cancer Res. 2018
27903463 HER2 Transmembrane Domain (TMD) Mutations (V659/G660) That Stabilize Homo- and Heterodimerization Are Rare Oncogenic Drivers in Lung Adenocarcinoma That Respond to Afatinib

Gitlitz, BJ, Klempner, SJ, Ali, SM, Steinecker, G, Ou, SI, Bocharov, EV, Suh, JH, Ross, JS, Johnson, M, Haddad, CK, Chung, J, Schrock, AB, Velcheti, V, Campregher, PV, Stephens, PJ, Miller, VA

J Thorac Oncol 2017
23948973 Human breast cancer cells harboring a gatekeeper T798M mutation in HER2 overexpress EGFR ligands and are sensitive to dual inhibition of EGFR and HER2

Song, Y, Estrada, MV, Arteaga, CL, Chakrabarty, A, Narasanna, A, Ghosh, R, Rexer, BN, Engelman, JA

Clin. Cancer Res. 2013
23220880 Activating HER2 mutations in HER2 gene amplification negative breast cancer

Bose, R, Shen, W, Aronson, AB, Goel, N, Koboldt, DC, Li, S, Searleman, AC, Ma, CX, Ellis, MJ, Shen, D, Ding, L, Monsey, J, Mardis, ER, Kavuri, SM

Cancer Discov 2013
21638049 In situ detection of HER2:HER2 and HER2:HER3 protein-protein interactions demonstrates prognostic significance in early breast cancer

Mallon, EA, Cameron, DA, Munro, AF, Twelves, CJ, Cunningham, CA, Taylor, KJ, Bartlett, JM, Thomas, J, Spears, M

Breast Cancer Res. Treat. 2012
31292270 Emergence of ERBB2 Mutation as a Biomarker and an Actionable Target in Solid Cancers

Masood, A, Katta, A, Kancha, RK, Subramanian, J, Vudem, DR

Oncologist 2019
18978815 Comparison of 3D and 2D tumor models reveals enhanced HER2 activation in 3D associated with an increased response to trastuzumab

Pickl, M, Ries, CH

Oncogene 2009
26375550 Tumor driven by gain-of-function HER2 H878Y mutant is highly sensitive to HER2 inhibitor

Xi, R, Hu, Z, Liu, X, Xie, Q, Chen, L, Zhang, A, Liu, D, Hu, Y

Oncotarget 2015
22908275 Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2

Walker, SR, Greulich, H, Pho, NH, Banerji, S, Berger, AH, Lawrence, MS, Getz, G, Frank, D, Tanaka, KE, Chen, TH, Mani, DR, Liao, R, Imielinski, M, Winckler, W, Lee, SH, Meyerson, M, Hahn, WC, Wong, KK, Ambrogio, L, Kaplan, B, Cho, J, Mertins, P, Carr, SA, Jaffe, JD, Zhang, X, Eck, MJ, Yun, CH, Zhang, J

Proc. Natl. Acad. Sci. U.S.A. 2012
22046346 Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib

Duyster, J, Kancha, RK, Engh, RA, Peschel, C, Bartosch, N, von Bubnoff, N

PLoS ONE 2011
23843458 Carboxyl group footprinting mass spectrometry and molecular dynamics identify key interactions in the HER2-HER3 receptor tyrosine kinase interface

Monsey, J, Collier, TS, Diraviyam, K, Sept, D, Shen, W, Bose, R

J. Biol. Chem. 2013
30449325 Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations

Antony, A, Khanna-Gupta, A, Singh, A, Pahuja, KB, Kljavin, NM, Bueno, R, Chougule, A, Dutt, A, Phalke, S, Prabhash, K, Gupta, R, Ziai, J, Banavali, SD, Kumar, P, Trivedi, V, Seshagiri, S, Jaiswal, BS, Nguyen, TT, DeGrado, WF, Ramprasad, V, Vargas, D, Senger, K, Chaudhuri, S, Sokol, ES, Trabucco, SE, Patil, V, Joshi, A, Thaker, TM, Noronha, V, Hartmaier, RJ, Durinck, S, Mravic, M, Stawiski, EW, Jura, N

Cancer Cell 2018
28274957 An Acquired HER2T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer

Hyman, DM, Solit, DB, Nagy, R, Sheehan, JH, Sliwoski, GR, Berger, MF, He, J, Lalani, AS, Brewer, MR, Miller, V, Cross, D, Cutler, RE, Hanker, AB, Lanman, R, Arteaga, CL, Koch, JP, Lovly, CM, Meiler, J

Cancer Discov 2017
25853726 Phosphorylation of mutationally introduced tyrosine in the activation loop of HER2 confers gain-of-function activity

Hao, R, Wang, P, Hu, Z, Li, L, Zhang, A, Chen, S, Gao, Y, Luan, Z, Zhang, H, Huang, N, Wan, X, Wei, M, Xie, Q, Chen, L, Li, L

PLoS ONE 2015
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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