Signaling by ERBB2 TMD/JMD mutants

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R-HSA-9665686
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Homo sapiens
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Recurrent missense mutations in regions encoding the transmembrane domain (TMD) and the juxtamembrane domain (JMD) are frequently reported in cancer. The ERBB2 TMD mutants include ERBB2 V659E, ERBB2 V659K, ERBB2 G660D, ERBB2 G660R, ERBB2 S653C, ERBB2 R677L and ERBB2 R678Q. The ERBB2 JMD mutants include ERBB2 E693K and ERBB2 Q709L. ERBB2 TMD mutants ERBB2 V659E, ERBB2 G660D and S653C (de Martino et al. 2014) are known to be activating. ERBB2 TMD/JMD mutants ERBB2 R678Q, ERBB2 E693K, and ERBB2 Q709L mutations may be activating when co-expressed with a wild type ERBB2 receptor (Pahuja et al. 2018). TMD and JMD mutations can activate ERBB2 signaling by improving the active dimer interface or by stabilizing the active conformation. TMD/JMD mutants that are activating in the presence of wild type ERBB2, such as ERBB2 R678Q, may form homodimers with the wild type ERBB2 (Pahuja et al. 2018).

Based on trans-autophosphorylation of ERBB2 and its dimerization partners EGFR and ERBB3, the following ERBB2 TMD/JMD mutants are assumed to form heterodimers with EGFR and ERBB3:
ERBB2 S653C (de Martino et al. 2014)
ERBB2 R678Q (Bose et al. 2013, Pahuja et al. 2018).

Phosphorylation of tyrosine residues in the C-tail of ERBB2 was shown for the following ERBB2 TMD/JMD mutants:
ERBB2 V659E (Pahuja et al. 2018);
ERBB2 V659K (Pahuja et al. 2018);
ERBB2 G660D (Pahuja et al. 2018);
ERBB2 G660R (Pahuja et al. 2018);
ERBB2 S653C (de Martino et al. 2014 - phosphorylation at Y1248 demonstrated);
ERBB2 R677L (Pahuja et al. 2018);
ERBB2 R678Q (Bose et al. 2013; de Martino et al. 2014 - phosphorylation at Y1248 demonstrated; Pahuja et al. 2018); ERBB2 Q709L (Pahuja et al. 2018)

Phosphorylation of tyrosine residues in the C-tail of EGFR was demonstrated for ERBB2 S653C (de Martino et al. 2014 - phosphorylation at Y1068) and ERBB2 R678Q (Bose et al. 2013; de Martino et al. 2014 - phosphorylation at Y1068).

Phosphorylation of tyrosine residues in the C-tail of ERBB3 was demonstrated for ERBB2 S653C (de Martino et al. 2014 - phosphorylation at Y1197) and ERBB2 R678Q (Bose et al. 2013; de Martino et al. 2014 - phosphorylation at Y1197).

Activation of downstream RAS signaling was shown for ERBB2 S653C (de Martino et al. 2014) and ERBB2 R678Q (Bose et al. 2013, de Martino et al. 2014) through activating tyrosine phosphorylation on ERKs (MAPK1 and MAPK3) and SHC1.

Activation of downstream PLCG1 signaling was demonstrated for ERBB2 R678Q, through activating tyrosine phosphorylation on PLCG1 (Bose et al. 2013).

Activation of PI3K/AKT signaling by ERBB2 TMD/JMD mutants has not been tested.

Signaling by ERBB2 V659K, ERBB2 G660D, ERBB2 G660R, ERBB2 R677L, ERBB2 E693K and ERBB2 Q709L has not been sufficiently studied and they are annotated as candidates.

The following ERBB2 TMD/JMD mutants are sensitive to the therapeutic antibody trastuzumab (herceptin):
ERBB2 V659E (Pahuja et al. 2018);
ERBB2 G660D (Pahuja et al. 2018);
ERBB2 G660R (Pahuja et al. 2018);
ERBB2 R678Q (Bose et al. 2013, Pahuja et al. 2018);
ERBB2 Q709L (Pahuja et al. 2018);

With respect to pertuzumab, a therapeutic antibody that block ligand-driven heterodimerization of ERBB2, ERBB2 R678Q is sensitive to pertuzumab, while ERBB2 V659E, ERBB2 G660D, ERBB2 G660R and probably ERBB2 Q709L are resistant (Pahuja et al. 2018).

The following ERBB2 TMD/JMD mutants are sensitive to lapatinib:
ERBB2 S653C (de Martino et al. 2014);
ERBB2 R678Q (Bose et al. 2013);

The following ERBB2 TMD/JMD mutants are sensitive to neratinib:
ERBB2 V659E (Pahuja et al. 2018);
ERBB2 G660D (Pahuja et al. 2018);
ERBB2 G660R (Pahuja et al. 2018);
ERBB2 R678Q (Bose et al. 2013, Pahuja et al. 2018);
ERBB2 Q709L (Pahuja et al. 2018);

The following ERBB2 TMD/JMD mutants are sensitive to afatinib:
ERBB2 G660D (Pahuja et al. 2018);
ERBB2 G660R (Pahuja et al. 2018);
ERBB2 S653C (de Martino et al. 2014);
ERBB2 R678Q (Pahuja et al. 2018);
ERBB2 Q709L (Pahuja et al. 2018).

Literature References
PubMed ID Title Journal Year
30449325 Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations

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

Cancer Cell 2018
24971884 Impact of ERBB2 mutations on in vitro sensitivity of bladder cancer to lapatinib

de Martino, M, Zhuang, D, Klatte, T, Rieken, M, RouprĂȘt, M, Xylinas, E, Clozel, T, Krzywinski, M, Elemento, O, Shariat, SF

Cancer Biol. Ther. 2014
23220880 Activating HER2 mutations in HER2 gene amplification negative breast cancer

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

Cancer Discov 2013
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Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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