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

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.

doi:10.1016/j.ccell.2019.09.001

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

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 +23 more·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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Most second-generation TKIs are dosed at the maximum tolerated doses, resulting in plasma concentrations 10-100 fold greater than concentrations necessary for inhibiting PACC mutations.
“Clinically, second-generation TKIs have been associated with inhibition of wild-type EGFR and related adverse events15,35,36; however, most second-generation TKIs are dosed at the maximum tolerated doses, resulting in plasma concentrations 10–100 fold greater than concentrations necessary for inhibiting PACC mutations.”
From Structure-based classification predicts drug response in EGFR-mutant NSCLC (2021) · cites this paper as [36]

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Atomistic insights into the lung cancer-associated L755P mutation in HER2 resistance to lapatinib: a molecular dynamics study
Yang, B., Zhang, H., & Wang, H. (2015) · Journal of Molecular Modeling · doi:10.1007/s00894-015-2580-x · Cited by 18 · see citing works
A systematic analysis of the resistance and sensitivity of HER2YVMAreceptor tyrosine kinase mutant to tyrosine kinase inhibitors in HER2-positive lung cancer
Shen, X., Chen, B., Ma, Z., Xie, B., Cao, X., Yang, T., Zhao, Y., Qin, J., Li, J., Cao, F., et al. (2015) · Journal of Receptors and Signal Transduction · doi:10.3109/10799893.2015.1049361 · Cited by 10 · see citing works
Metastatic Breast Cancer Patient With Activating HER2 Exon 20 Insertion Mutation With Response to Poziotinib: Case Report of Compassionate Drug Use
Pandey, A. K., & Brufsky, A. (2018) · Clinical Breast Cancer · doi:10.1016/j.clbc.2018.09.010 · Cited by 4 · see citing works
In the literature: December 2019
Gambardella, V., Insa, A., Cejalvo, J. M., & Cervantes, A. M. R. (2020) · ESMO Open · doi:10.1136/esmoopen-2019-000642 · Cited by 1 · see citing works

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Trastuzumab Deruxtecan in HER2 -Mutant Non–Small-Cell Lung Cancer
Li, B. T., Smit, E. F., Goto, Y., Nakagawa, K., Udagawa, H., Mazières, J., Nagasaka, M., Bazhenova, L. A., Saltos, A. N., Felip, E., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2112431 · Cited by 1,046 · see citing works
Structure-based classification predicts drug response in EGFR-mutant NSCLC
Robichaux, J. P., Le, X., Vijayan, R. S. K., Hicks, J. K., Heeke, S., Elamin, Y. Y., Lin, H. Y., Udagawa, H., Skoulidis, F., Tran, H., et al. (2021) · Nature · doi:10.1038/s41586-021-03898-1 · Cited by 490 · see citing works
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Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors
Tsurutani, J., Iwata, H., Krop, I. E., Janne, P. A., Doi, T., Takahashi, S., Park, H., Redfern, C. H., Tamura, K., Wise-Draper, T. M., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-1014 · Cited by 356 · see citing works
HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers
Li, B. T., Michelini, F., Misale, S., Cocco, E., Baldino, L., Cai, Y., Shifman, S. G., Tu, H., Myers, M. L., Xu, C., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0215 · Cited by 288 · see citing works
Endocytosis in cancer and cancer therapy
Banushi, B., Joseph, S. R., Lum, B., Lee, J. J., & Simpson, F. (2023) · Nature reviews. Cancer · doi:10.1038/s41568-023-00574-6 · Cited by 245 · see citing works
Current Landscape of Non-Small Cell Lung Cancer: Epidemiology, Histological Classification, Targeted Therapies, and Immunotherapy
Rodak, O., Peris‐Díaz, M. D., Olbromski, M., Podhorska‐Okołów, M., & Dzięgiel, P. (2021) · Cancers · doi:10.3390/cancers13184705 · Cited by 237 · see citing works
Antibody–drug conjugates: in search of partners of choice
Fuentes‐Antrás, J., Genta, S., Vijenthira, A., & Siu, L. L. (2023) · Trends in cancer · doi:10.1016/j.trecan.2023.01.003 · Cited by 202 · see citing works
Targeting HER2 in non-small-cell lung cancer (NSCLC): a glimpse of hope? An updated review on therapeutic strategies in NSCLC harbouring HER2 alterations
Riudavets, M., Sullivan, I., Abdayem, P., & Planchard, D. (2021) · ESMO Open · doi:10.1016/j.esmoop.2021.100260 · Cited by 196 · see citing works
EGFR and HER2 exon 20 insertions in solid tumours: from biology to treatment
Friedlaender, A., Subbiah, V., Russo, A., Banna, G. L., Malapelle, U., Rolfo, C. D., & Addeo, A. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00558-1 · Cited by 203 · see citing works
Emerging Targeted Therapies for HER2-Positive Breast Cancer
Mercogliano, M. F., Bruni, S., Mauro, F. L., & Schillaci, R. (2023) · Cancers · doi:10.3390/cancers15071987 · Cited by 203 · see citing works
The promise and challenges of combination therapies with antibody-drug conjugates in solid tumors
Wei, Q., Li, P., Yang, T. K., Zhu, J., Sun, L., Zhang, Z., Wang, L., Tian, X., Chen, J., Hu, C., et al. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-023-01509-2 · Cited by 169 · see citing works
Poziotinib in Non–Small-Cell Lung Cancer Harboring HER2 Exon 20 Insertion Mutations After Prior Therapies: ZENITH20-2 Trial
Le, X., Cornelissen, R., Garassino, M. C., Clarke, J. M., Tchekmedyian, N., Goldman, J. W., Leu, S.-Y., Bhat, G., Lebel, F. M., Heymach, J. V., et al. (2021) · Journal of Clinical Oncology · doi:10.1200/jco.21.01323 · Cited by 165 · see citing works
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Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma
Kim, S.-Y., Kim, S.-M., Lim, S., Lee, J. Y., Choi, S.-J., Yang, S.-D., Yun, M. R., Kim, C. G., Gu, S. R., Park, C., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-5026 · Cited by 151 · see citing works
HER2-targeted therapies in cancer: a systematic review
Zhu, K., Yang, X., Tai, H., Zhong, X., Luo, T., & Zheng, H. Y. (2024) · Biomarker Research · doi:10.1186/s40364-024-00565-1 · Cited by 143 · see citing works
HER2-positive advanced breast cancer treatment in 2020
Cesca, M. G., Vian, L., Cristóvão‐Ferreira, S., Ponde, N. F., & de Azambuja, E. (2020) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2020.102033 · Cited by 127 · see citing works
Consensus for HER2 alterations testing in non-small-cell lung cancer
Ren, S., Wang, J., Ying, J., Mitsudomi, T., Lee, D., Wang, Z., Chu, Q., Mack, P. C., Cheng, Y., Duan, J., et al. (2022) · ESMO Open · doi:10.1016/j.esmoop.2022.100395 · Cited by 124 · see citing works
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Zongertinib in Previously Treated HER2 -Mutant Non–Small-Cell Lung Cancer
Heymach, J. V., Ruiter, G., Ahn, M.-J., Girard, N., Smit, E. F., Planchard, D., Wu, Y.-L., Cho, B. C., Yamamoto, N., Sabari, J. K., et al. (2025) · New England Journal of Medicine · doi:10.1056/nejmoa2503704 · Cited by 118 · see citing works
Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity
Elamin, Y. Y., Robichaux, J. P., Carter, B. W., Altan, M., Tran, H. T., Gibbons, D. L., Heeke, S., Fossella, F. V., Lam, V. K. L., Le, X., et al. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.06.006 · Cited by 110 · see citing works
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Co-Occurring Gain-of-Function Mutations in HER2 and HER3 Modulate HER2/HER3 Activation, Breast Cancer Progression, and HER2 Inhibitor Sensitivity
Hanker, A. B., Brown, B. P., Meiler, J., Marín, A., Jayanthan, H. S., Ye, D., Lin, C.-C. A., Akamatsu, H., Lee, K., Chatterjee, S., et al. (2020) · Cancer Cell · doi:10.1016/j.ccell.2021.06.001 · Cited by 104 · see citing works
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Poziotinib for Patients With HER2 Exon 20 Mutant Non–Small-Cell Lung Cancer: Results From a Phase II Trial
Elamin, Y. Y., Robichaux, J. P., Carter, B. W., Altan, M., Gibbons, D. L., Fossella, F. V., Lam, V. K. L., Patel, A. B., Negrao, M. V., Le, X., et al. (2021) · Journal of Clinical Oncology · doi:10.1200/jco.21.01113 · Cited by 99 · see citing works
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Antibody-drug conjugates: A promising novel therapeutic approach in lung cancer
Desai, A. P., Abdayem, P., Adjei, A. A., & Planchard, D. (2021) · Lung Cancer · doi:10.1016/j.lungcan.2021.12.002 · Cited by 89 · see citing works
The force of HER2 – A druggable target in NSCLC?
Jebbink, M., Langen, A. J. D., Boelens, M. C., Monkhorst, K., & Smit, E. F. (2020) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2020.101996 · Cited by 84 · see citing works
Combination of Trastuzumab, Pertuzumab, and Docetaxel in Patients With Advanced Non–Small-Cell Lung Cancer Harboring HER2 Mutations: Results From the IFCT-1703 R2D2 Trial
Mazières, J., Lafitte, C., Ricordel, C., Greillier, L., Negre, E., Zalcman, G., Domblides, C., Madelaine, J., Bennouna, J., Mascaux, C., et al. (2022) · Journal of Clinical Oncology · doi:10.1200/jco.21.01455 · Cited by 84 · see citing works
Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer
Gaibar, M., Beltrán, L., Romero‐Lorca, A., Fernández‐Santander, A., & Novillo, A. (2020) · Journal of Oncology · doi:10.1155/2020/6375956 · Cited by 81 · see citing works
Efficacy and safety of pyrotinib in advanced lung adenocarcinoma with HER2 mutations: a multicenter, single-arm, phase II trial
Song, Z., Li, Y., Chen, S., Ying, S., Xu, S., Huang, J., Wu, D., Lv, D., Bei, T., Liu, S., et al. (2022) · BMC Medicine · doi:10.1186/s12916-022-02245-z · Cited by 68 · see citing works
Novel drugs targeting EGFR and HER2 exon 20 mutations in metastatic NSCLC
Baraibar, I., Mezquita, L., Bazo, I. G., & Planchard, D. (2020) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2020.102906 · Cited by 66 · see citing works
Sevabertinib in Advanced HER2 -Mutant Non–Small-Cell Lung Cancer
Le, X., Kim, T. M., Loong, H. H., Prelaj, A., Goh, B. C., Li, L., Fang, Y., Lu, S., Dong, X., Wu, L., et al. (2025) · New England Journal of Medicine · doi:10.1056/nejmoa2511065 · Cited by 70 · see citing works
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HER family in cancer progression: From discovery to 2020 and beyond
Kumar, R., George, B., Campbell, M. R., Verma, N., Paul, A. M., Melo-Alvim, C., Ribeiro, L., Pillai, M. R., Costa, L., & Moasser, M. M. (2020) · Advances in cancer research · doi:10.1016/bs.acr.2020.04.001 · Cited by 66 · see citing works
Poziotinib in Treatment-Naive NSCLC Harboring HER2 Exon 20 Mutations: ZENITH20-4, A Multicenter, Multicohort, Open-Label, Phase 2 Trial (Cohort 4)
Cornelissen, R., Prelaj, A., Sun, S. B., Baik, C. S., Wollner, M., Haura, E. B., Mamdani, H. M., Riess, J. W., Cappuzzo, F., Garassino, M. C., et al. (2023) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2023.03.016 · Cited by 62 · see citing works
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Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer
Rebuzzi, S. E., Zullo, L., Rossi, G., Grassi, M., Murianni, V., Tagliamento, M., Prelaj, A., Coco, S., Longo, L., Bello, M. G. D., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052625 · Cited by 61 · see citing works
Discovery of potent and selective HER2 inhibitors with efficacy against HER2 exon 20 insertion-driven tumors, which preserve wild-type EGFR signaling
Wilding, B., Scharn, D., Böse, D., Baum, A., Santoro, V., Chetta, P., Schnitzer, R., Botesteanu, D., Reiser, C., Kornigg, S., et al. (2022) · Nature Cancer · doi:10.1038/s43018-022-00412-y · Cited by 58 · see citing works
A review of HER2 overexpression and somatic mutations in cancers
Galogre, M. I., Rodin, D., Pyatnitskiy, M. A., Mackelprang, M., & Koman, I. E. (2023) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2023.103997 · Cited by 60 · see citing works
Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib
Han, H., Li, S., Chen, T., Fitzgerald, M., Liu, S., Peng, C., Tang, K. H., Cao, S., Chouitar, J., Wu, J., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-21-1526 · Cited by 57 · see citing works
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A single arm phase Ib/II trial of first-line pembrolizumab, trastuzumab and chemotherapy for advanced HER2-positive gastric cancer
Lee, C., Rha, S. Y., Kim, H. S., Jung, M., Kang, B., Che, J., Kwon, W. S., Park, S., Bae, W. K., Koo, D., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33267-z · Cited by 58 · see citing works
Poziotinib for EGFR and HER2 exon 20 insertion mutation in advanced NSCLC: Results from the expanded access program
Prelaj, A., Bottiglieri, A., Proto, C., Russo, G. L., Signorelli, D., Ferrara, R., Galli, G., Toma, A. D., Viscardi, G., Brambilla, M., et al. (2021) · European Journal of Cancer · doi:10.1016/j.ejca.2021.02.038 · Cited by 57 · see citing works
Pathway-Based Drug-Repurposing Schemes in Cancer: The Role of Translational Bioinformatics
Lemus, E. H., & Martínez-García, M. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2020.605680 · Cited by 55 · see citing works
Management of HER2 alterations in non-small cell lung cancer – The past, present, and future
Nützinger, J., Lee, J. B., Low, J. L., Chia, P. L., Wijaya, S. T., Cho, B. C., Lim, S. M., & Soo, R. A. (2023) · Lung Cancer · doi:10.1016/j.lungcan.2023.107385 · Cited by 50 · see citing works
HER2-Selective Tyrosine Kinase Inhibitor, Zongertinib (BI 1810631), in Patients With Advanced/Metastatic Solid Tumors With HER2 Alterations: A Phase Ia Dose-Escalation Study
Heymach, J. V., Opdam, F. L., Barve, M. A., Tu, H., Wu, Y.-L. L. C., Berz, D., Schröter, L., Botilde, Y., Sadrolhefazi, B., Serra, J., et al. (2025) · Journal of Clinical Oncology · doi:10.1200/jco-24-01727 · Cited by 54 · see citing works
Conformational Landscapes of HER2 Exon 20 Insertions Explain Their Sensitivity to Kinase Inhibitors in Lung Adenocarcinoma
Zhao, S., Fang, W., Pan, H., Yang, Y., Liang, Y., Yang, L., Dong, X., Zhan, J., Wang, K., & Zhang, L. (2020) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2020.01.020 · Cited by 45 · see citing works
Caveolin-1 temporal modulation enhances antibody drug efficacy in heterogeneous gastric cancer
Pereira, P. M. R., Mandleywala, K., Monette, S., Lumish, M. A., Tully, K. M., Panikar, S. S., Cornejo, M., Mauguen, A., Ragupathi, A., Keltee, N., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-30142-9 · Cited by 44 · see citing works
Use of Ex Vivo Patient-Derived Tumor Organotypic Spheroids to Identify Combination Therapies for HER2 Mutant Non–Small Cell Lung Cancer
Ivanova, E. V., Kuraguchi, M., Xu, M., Portell, A. J., Taus, L. J., Diala, I., Lalani, A. S., Choi, J., Chambers, E. S., Li, S., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-1844 · Cited by 45 · see citing works
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A Novel HER2-Selective Kinase Inhibitor Is Effective in HER2 Mutant and Amplified Non–Small Cell Lung Cancer
Son, J., Jang, J., Beyett, T. S., Eum, Y., Haikala, H. M., Verano, A. L., Lin, M., Hatcher, J. M., Kwiatkowski, N. P., Eser, P. Ö., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-21-2693 · Cited by 43 · see citing works
HER2 targeted therapy in colorectal cancer: New horizons
Suwaidan, A. A., Lau, D. K., & Chau, I. (2022) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2022.102363 · Cited by 43 · see citing works
HER2-Altered Non-Small Cell Lung Cancer: Biology, Clinicopathologic Features, and Emerging Therapies
Yu, X., Ji, X., & Su, C. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.860313 · Cited by 43 · see citing works
A Promising New Model: Establishment of Patient‐Derived Organoid Models Covering HPV‐Related Cervical Pre‐Cancerous Lesions and Their Cancers
Hu, B., Wang, R., Wu, D., Long, R., Fan, J., Hu, Z., Hu, X., Ma, D., Li, F., Sun, C., et al. (2024) · Advanced Science · doi:10.1002/advs.202302340 · Cited by 38 · see citing works
Discovery of potent and selective HER2 PROTAC degrader based Tucatinib with improved efficacy against HER2 positive cancers
Hu, M., Li, Y., Li, J., Zhou, H., Liu, C., Liu, Z., Gong, Y., Ying, B., & Xie, Y. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114775 · Cited by 39 · see citing works
HER2 heterogeneity and treatment response–associated profiles in HER2-positive breast cancer in the NCT02326974 clinical trial
冨松, 京., Metzger, O., Viale, G., dell’Orto, P., Russo, L., Goyette, M.-A., Kamat, A., Yardley, D. A., Abramson, V. G., Arteaga, C. L., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci176454 · Cited by 36 · see citing works
Predicting Response to Antibody Drug Conjugates: A Focus on Antigens’ Targetability
Ascione, L., Crimini, E., Trapani, D., Marra, A., Criscitiello, C., & Curigliano, G. (2023) · The Oncologist · doi:10.1093/oncolo/oyad246 · Cited by 33 · see citing works
Targeting HER2 genomic alterations in non-small cell lung cancer
Zeng, J., Ma, W., Young, R. B., & Li, T. (2021) · Journal of the National Cancer Center · doi:10.1016/j.jncc.2021.04.001 · Cited by 35 · see citing works
If it’s a target, it’s a pan-cancer target: Tissue is not the issue
Adashek, J. J., Kato, S., Sicklick, J. K., Lippman, S. M., & Kurzrock, R. (2024) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2024.102721 · Cited by 32 · see citing works
Spotlight on Trastuzumab Deruxtecan (DS-8201,T-DXd) for HER2 Mutation Positive Non-Small Cell Lung Cancer
Azar, I. H., Alkassis, S., Fukui, J. A., Alsawah, F., Fedak, K., Hallak, M. N. A., Sukari, A. W., & Nagasaka, M. (2021) · Lung Cancer Targets and Therapy · doi:10.2147/lctt.s307324 · Cited by 34 · see citing works
Design, Synthesis, Analysis, Evaluation of Cytotoxicity Against MCF-7 Breast Cancer Cells, 3D QSAR Studies and EGFR, HER2 Inhibition Studies on Novel Biginelli 1,4-Dihydropyrimidines
Naishima, N. L., Faizan, S., Raju, R. M., Sruthi, A. S. V. L., Veena, N. G., Sharma, G. K., Vasanth, K. S., Shivaraju, V. K., Ramu, R., & Kumar, B. R. P. (2022) · Journal of Molecular Structure · doi:10.1016/j.molstruc.2022.134848 · Cited by 29 · see citing works
The clinical development of antibody-drug conjugates for non-small cell lung cancer therapy
Liu, X., Deng, J., Zhang, R., Xing, J., Wu, Y., Chen, W., Liang, B., Xing, D., Xu, J., & Zhang, M. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1335252 · Cited by 28 · see citing works
ERBB2/HER2 mutations are transforming and therapeutically targetable in leukemia
Joshi, S. K., Keck, J. M., Eide, C. A., Bottomly, D., Traer, E. A., Tyner, J. W., McWeeney, S. K., Tognon, C. E., & Druker, B. J. (2020) · Leukemia · doi:10.1038/s41375-020-0844-7 · Cited by 28 · see citing works
The Evolving Landscape of HER2-Directed Breast Cancer Therapy
Marti, J. L. G., Hyder, T., Nasrazadani, A., & Brufsky, A. (2020) · Current Treatment Options in Oncology · doi:10.1007/s11864-020-00780-6 · Cited by 27 · see citing works
Molecular charcterization of lung adenocarcinoma combining whole exome sequencing, copy number analysis and gene expression profiling
Testa, U., Pelosi, E., & Castelli, G. (2021) · Expert Review of Molecular Diagnostics · doi:10.1080/14737159.2022.2017774 · Cited by 28 · see citing works
Acquired Secondary HER2 Mutations Enhance HER2/MAPK Signaling and Promote Resistance to HER2 Kinase Inhibition in Breast Cancer
Marín, A., Mamun, A. A., Patel, H. M., Akamatsu, H., Ye, D., Sudhan, D. R., Eli, L. D., Marcelain, K., Brown, B. P., Meiler, J., et al. (2023) · Cancer Research · doi:10.1158/0008-5472.can-22-3617 · Cited by 29 · see citing works
HER2 Mutations in Non–Small Cell Lung Cancer: A Herculean Effort to Hit the Target
Rolfo, C. D., & Russo, A. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0225 · Cited by 27 · see citing works
Efficacy of targeted therapy in patients with HER2‐positive non‐small cell lung cancer: A systematic review and meta‐analysis
Wu, H., Zhuo, K., & Wang, K. (2021) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.15155 · Cited by 26 · see citing works
Targeted Approaches to HER2-Low Breast Cancer: Current Practice and Future Directions
Lai, H.-Z., Han, J., Fu, X., Ren, Y., Li, Z., & You, F.-M. (2022) · Cancers · doi:10.3390/cancers14153774 · Cited by 27 · see citing works
Emerging Role of ERBB2 in Targeted Therapy for Metastatic Colorectal Cancer: Signaling Pathways to Therapeutic Strategies
Wang, N., Cao, Y., Si, C., Shao, P., Su, G., Wang, X., Bao, J., & Liu, Y. (2022) · Cancers · doi:10.3390/cancers14205160 · Cited by 27 · see citing works
The predictive role of ERBB2 point mutations in metastatic colorectal cancer: A systematic review
Vaghi, C., Mauri, G., Agostara, A. G., Patelli, G., Pizzutilo, E. G., Nakamura, Y., Yoshino, T., Siena, S., & Bianchi, A. S. (2022) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2022.102488 · Cited by 27 · see citing works
Tucatinib and trastuzumab in HER2-mutated metastatic breast cancer: a phase 2 basket trial
Okines, A. F. C., Curigliano, G., Mizuno, N., Oh, D., Rorive, A., Soliman, H. H., Takahashi, S., Bekaii‐Saab, T., Burkard, M. E., Chung, K. Y., et al. (2025) · Nature Medicine · doi:10.1038/s41591-024-03462-0 · Cited by 28 · see citing works
Pan‐cancer analysis shapes the understanding of cancer biology and medicine
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Pan-cancer analysis identifies RNA helicase DDX1 as a prognostic marker
Gao, B., Li, X., Li, S., Wang, S., Wu, J., & Li, J. (2022) · Phenomics · doi:10.1007/s43657-021-00034-x · Cited by 25 · see citing works
Self-citation
Lung adenocarcinoma with ERBB2 exon 20 insertions: Comutations and immunogenomic features related to chemoimmunotherapy
Tian, P., Zeng, H., Ji, L., Ding, Z., Ren, L., Gao, W., Fan, Z., Lin, L., Le, X., Li, P., et al. (2021) · Lung Cancer · doi:10.1016/j.lungcan.2021.07.014 · Cited by 24 · see citing works
Self-citation
Sevabertinib, a Reversible HER2 Inhibitor with Activity in Lung Cancer
Siegel, F., Siegel, S., Kotýnková, K., Uzunbas, G. K., Korr, D., Tomono, H., Andersen, S., Denney, D. R., Berger, M., Schulze, V., et al. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-25-0605 · Cited by 28 · see citing works
Insight into Targeting Exon20 Insertion Mutations of the Epidermal Growth Factor Receptor with Wild Type-Sparing Inhibitors
Lategahn, J., Tumbrink, H. L., Schultz‐Fademrecht, C., Heimsoeth, A., Werr, L., Niggenaber, J., Keul, M., Parmaksiz, F., Baumann, M., Menninger, S., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c02080 · Cited by 23 · see citing works
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Abstract 347: Identification of poziotinib alone or in combination with TDM1 as a pan-HER2 inhibitor
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Abstract 4772: Poziotinib overcomes de novo resistance of HER2 exon 20 mutations in NSCLC and other cancers: Preclinical studies and initial clinical testing
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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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