Cited by 243HER2/EGFR in Cancer ResearchLung Cancer Treatments and MutationsCancer Genomics and Diagnostics

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Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity

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Robichaux, Jacqulyne P., Elamin, Yasir Y., Vijayan, R.S.K., Nilsson, Monique B., Hu, Lemei, He, Junqin, Zhang, Fahao, Pisegna, Marlese, Poteete, Alissa, Sun, Huiying, Li, Shuai, Chen, Ting, Han, Han, Negrao, Marcelo Vailati, Ahnert, Jordi Rodon, Diao, Lixia, Wang, Jing, Le, Xiuning, Meric-Bernstam, Funda, Routbort, Mark, Roeck, Brent, Yang, Zane, Raymond, Victoria M., Lanman, Richard B., Frampton, Garrett M., Miller, Vincent A., Schrock, Alexa B., Albacker, Lee A., Wong, Kwok-kin, Cross, Jason B., Heymach, John V.·2019·Cancer Cell

DOI 10.1016/j.ccell.2019.09.001PMC PMC6944069

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Abstract

We characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants yielded differential sensitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs) in vitro, and molecular dynamics simulations revealed that mutants with a reduced drug-binding pocket volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in ERBB2 exon 20-mutant non-small cell lung cancer resulted in a confirmed objective response rate of 42% in the first 12 evaluable patients. In pre-clinical models, poziotinib upregulated HER2 cell-surface expression and potentiated the activity of T-DM1, resulting in complete tumor regression with combination treatment.

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Authors: Robichaux, J. P., Elamin, Y. Y., Vijayan, R. S. K., Nilsson, M. B., Hu, L., He, J., Zhang, F., Pisegna, M., Poteete, A., Sun, H., Li, S., Chen, T., Han, H., Negrao, M. V., Ahnert, J. R., Diao, L., Wang, J., Le, X., Meric-Bernstam, F., Routbort, M., Roeck, B., Yang, Z., Raymond, V. M., Lanman, R. B., Frampton, G. M., Miller, V. A., Schrock, A. B., Albacker, L. A., Wong, K.-K., Cross, J. B., & Heymach, J. V.
Affiliations: The University of Texas MD Anderson Cancer Center (US)
NYU Langone Health (US)
Spectrum Pharmaceuticals (United States) (US)
Guardant (United States) (US)
Foundation Medicine (United States) (US)
Corresponding author: Heymach, John V.
ORCID: Robichaux, Jacqulyne P.
Elamin, Yasir Y.
Vijayan, R.S.K.
Nilsson, Monique B.
He, Junqin
Zhang, Fahao
Poteete, Alissa
Sun, Huiying
Li, Shuai
Chen, Ting
Han, Han
Negrao, Marcelo Vailati
Diao, Lixia
Wang, Jing
Le, Xiuning
Raymond, Victoria M.
Lanman, Richard B.
Frampton, Garrett M.
Miller, Vincent A.
Schrock, Alexa B.
Albacker, Lee A.
Wong, Kwok-kin
Cross, Jason B.
Heymach, John V.
Venue: Cancer Cell
Publisher: Elsevier BV
Published: 2019-10
Volume: 36
Issue: 4
Pages: 444-457.e7
ISSN: 1535-6108 (ISSN-L)
DOI: 10.1016/j.ccell.2019.09.001
PMC: PMC6944069
OpenAlex: W2977889895
Cited by: 242
References: 66
Citations by year: 2026: 21 · 2025: 34 · 2024: 33 · 2023: 40 · 2022: 43 · 2021: 43 · 2020: 28
FWCI: 12.00
Type: journal article
Language: en
Update notices: erratum (2020-03-16)
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 379 d)
Locations: Cancer Cell (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute
Topics: Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords: ERBB2 mutations, HER2, poziotinib, tyrosine kinase inhibitors, trastuzumab emtansine, non-small cell lung cancer, drug sensitivity, molecular dynamics simulation, drug-binding pocket, combination therapy
MeSH terms: Antineoplastic Agents, Immunological, Progression-Free Survival, Ado-Trastuzumab Emtansine, Adult, Animals, Antineoplastic Combined Chemotherapy Protocols, Disease Models, Animal, DNA Mutational Analysis, Drug Synergism, Female, Humans, Male, Mice, Transgenic, Mutation, Neoplasms, Quinazolines, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, Mice, Datasets as Topic

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Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity

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