Resistant ERBB2 KD mutants do not bind lapatinib

Stable Identifier
Reaction [transition]
Homo sapiens
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The following ERBB2 KD mutants are resistant to lapatinib:
ERBB2 L755P (Kancha et al. 2011; Yang et al. 2015 - the L755P substitution results in a structural change that makes binding to lapatinib energetically unfavorable; Nagano et al. 2018);
ERBB2 L755S (Kancha et al. 2011, Bose et al. 2013, Cocco et al. 2018, Nagano et al. 2018);
ERBB2 D769Y (Bose et al. 2013; partial sensitivity reported by Nagano et al. 2018);
ERBB2 T798I (Trowe et al. 2008);
ERBB2 T798M (Kancha et al. 2011, Rexer et al. 2013, Hanker et al. 2017);
ERBB2 T733I (Trowe et al. 2008);
ERBB2 V842I (Bose et al. 2013, Nagano et al. 2018);
ERBB2 L869R (Hanker et al. 2017);
One study reported sensitivity of ERBB2 I767M, ERBB2 P780_Y781insGSP and ERBB2 R896C to lapatinib (Nagano et al. 2018), while another study reported resistance (Bose et al. 2013).

Literature References
PubMed ID Title Journal Year
18413839 EXEL-7647 inhibits mutant forms of ErbB2 associated with lapatinib resistance and neoplastic transformation

Trowe, T, Boukouvala, S, Calkins, K, Cutler, RE, Fong, R, Funke, R, Gendreau, SB, Kim, YD, Miller, N, Woolfrey, JR, Vysotskaia, V, Yang, JP, Gerritsen, ME, Matthews, DJ, Lamb, P, Heuer, TS

Clin. Cancer Res. 2008
25620423 Atomistic insights into the lung cancer-associated L755P mutation in HER2 resistance to lapatinib: a molecular dynamics study

Yang, B, Zhang, H, Wang, H

J Mol Model 2015
22046346 Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib

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

PLoS ONE 2011
29967253 High-Throughput Functional Evaluation of Variants of Unknown Significance in ERBB2

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

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

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

Cancer Discov 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

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

Clin. Cancer Res. 2013
30301790 Neratinib is effective in breast tumors bearing both amplification and mutation of ERBB2 (HER2)

Cocco, E, Javier Carmona, F, Razavi, P, Won, HH, Cai, Y, Rossi, V, Chan, C, Cownie, J, Soong, J, Toska, E, Shifman, SG, Sarotto, I, Savas, P, Wick, MJ, Papadopoulos, KP, Moriarty, A, Cutler, RE, Avogadri-Connors, F, Lalani, AS, Bryce, RP, Chandarlapaty, S, Hyman, DM, Solit, DB, Boni, V, Loi, S, Baselga, J, Berger, MF, Montemurro, F, Scaltriti, M

Sci Signal 2018
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
Normal reaction
Functional status

Loss of function of ERBB2 KD mutants (lapatinib resistant):ERBIN:HSP90:CDC37 [plasma membrane]

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