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1. Supplementary Fig 6 from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Author

Maurizio Scaltriti, Charles M. Rudin, Neal Rosen, Elisa de Stanchina, Gary A. Ulaner, Junji Tsurutani, Ronglai Shen, John T. Poirier, Mark G. Kris, Maria E. Arcila, Pedram Razavi, Jorge S. Reis-Filho, Vicky Makker, Alan L. Ho, Darren J. Buonocore, Jason S. Lewis, David M. Hyman, Fabiola Cecchi, Anuja Bhalkikar, Wei-Li Liao, Sheeno Thyparambil, Helena A. Yu, David R. Jones, James M. Isbell, Michael Offin, Tony Ng, Paul R. Barber, Michael F. Berger, David B. Solit, Nancy U. Lin, Rachel A. Freedman, Irmina Diala, Alshad S. Lalani, Clare J. Wilhem, Gregory Weitsman, Besnik Qeriqi, Megan Little, Inna Khodos, Marissa Mattar, Chongrui Xu, Mackenzie L. Myers, Hai-Yan Tu, Sophie Shifman, Yanyan Cai, Laura Baldino, Emiliano Cocco, Sandra Misale, Flavia Michelini, and Bob T. Li

Abstract

Supplementary Fig 6

Published
2023
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2. Supplementary Fig 3 from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Author

Maurizio Scaltriti, Charles M. Rudin, Neal Rosen, Elisa de Stanchina, Gary A. Ulaner, Junji Tsurutani, Ronglai Shen, John T. Poirier, Mark G. Kris, Maria E. Arcila, Pedram Razavi, Jorge S. Reis-Filho, Vicky Makker, Alan L. Ho, Darren J. Buonocore, Jason S. Lewis, David M. Hyman, Fabiola Cecchi, Anuja Bhalkikar, Wei-Li Liao, Sheeno Thyparambil, Helena A. Yu, David R. Jones, James M. Isbell, Michael Offin, Tony Ng, Paul R. Barber, Michael F. Berger, David B. Solit, Nancy U. Lin, Rachel A. Freedman, Irmina Diala, Alshad S. Lalani, Clare J. Wilhem, Gregory Weitsman, Besnik Qeriqi, Megan Little, Inna Khodos, Marissa Mattar, Chongrui Xu, Mackenzie L. Myers, Hai-Yan Tu, Sophie Shifman, Yanyan Cai, Laura Baldino, Emiliano Cocco, Sandra Misale, Flavia Michelini, and Bob T. Li

Abstract

Supplementary Fig 3

Published
2023
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3. Supplementary Fig 2 from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Author

Maurizio Scaltriti, Charles M. Rudin, Neal Rosen, Elisa de Stanchina, Gary A. Ulaner, Junji Tsurutani, Ronglai Shen, John T. Poirier, Mark G. Kris, Maria E. Arcila, Pedram Razavi, Jorge S. Reis-Filho, Vicky Makker, Alan L. Ho, Darren J. Buonocore, Jason S. Lewis, David M. Hyman, Fabiola Cecchi, Anuja Bhalkikar, Wei-Li Liao, Sheeno Thyparambil, Helena A. Yu, David R. Jones, James M. Isbell, Michael Offin, Tony Ng, Paul R. Barber, Michael F. Berger, David B. Solit, Nancy U. Lin, Rachel A. Freedman, Irmina Diala, Alshad S. Lalani, Clare J. Wilhem, Gregory Weitsman, Besnik Qeriqi, Megan Little, Inna Khodos, Marissa Mattar, Chongrui Xu, Mackenzie L. Myers, Hai-Yan Tu, Sophie Shifman, Yanyan Cai, Laura Baldino, Emiliano Cocco, Sandra Misale, Flavia Michelini, and Bob T. Li

Abstract

Supplementary Fig 2

Published
2023
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4. Data from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Author

Maurizio Scaltriti, Charles M. Rudin, Neal Rosen, Elisa de Stanchina, Gary A. Ulaner, Junji Tsurutani, Ronglai Shen, John T. Poirier, Mark G. Kris, Maria E. Arcila, Pedram Razavi, Jorge S. Reis-Filho, Vicky Makker, Alan L. Ho, Darren J. Buonocore, Jason S. Lewis, David M. Hyman, Fabiola Cecchi, Anuja Bhalkikar, Wei-Li Liao, Sheeno Thyparambil, Helena A. Yu, David R. Jones, James M. Isbell, Michael Offin, Tony Ng, Paul R. Barber, Michael F. Berger, David B. Solit, Nancy U. Lin, Rachel A. Freedman, Irmina Diala, Alshad S. Lalani, Clare J. Wilhem, Gregory Weitsman, Besnik Qeriqi, Megan Little, Inna Khodos, Marissa Mattar, Chongrui Xu, Mackenzie L. Myers, Hai-Yan Tu, Sophie Shifman, Yanyan Cai, Laura Baldino, Emiliano Cocco, Sandra Misale, Flavia Michelini, and Bob T. Li

Abstract

Amplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody–drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2-amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy.Significance:T-DM1 is clinically effective in lung cancers with amplification of or mutations in ERBB2. This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy.See related commentary by Rolfo and Russo, p. 643.This article is highlighted in the In This Issue feature, p. 627

Published
2023
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5. Supplementary Fig 5 from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Author

Maurizio Scaltriti, Charles M. Rudin, Neal Rosen, Elisa de Stanchina, Gary A. Ulaner, Junji Tsurutani, Ronglai Shen, John T. Poirier, Mark G. Kris, Maria E. Arcila, Pedram Razavi, Jorge S. Reis-Filho, Vicky Makker, Alan L. Ho, Darren J. Buonocore, Jason S. Lewis, David M. Hyman, Fabiola Cecchi, Anuja Bhalkikar, Wei-Li Liao, Sheeno Thyparambil, Helena A. Yu, David R. Jones, James M. Isbell, Michael Offin, Tony Ng, Paul R. Barber, Michael F. Berger, David B. Solit, Nancy U. Lin, Rachel A. Freedman, Irmina Diala, Alshad S. Lalani, Clare J. Wilhem, Gregory Weitsman, Besnik Qeriqi, Megan Little, Inna Khodos, Marissa Mattar, Chongrui Xu, Mackenzie L. Myers, Hai-Yan Tu, Sophie Shifman, Yanyan Cai, Laura Baldino, Emiliano Cocco, Sandra Misale, Flavia Michelini, and Bob T. Li

Abstract

Supplementary Fig 5

Published
2023
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6. Supplementary Table 1 from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Author

Maurizio Scaltriti, Charles M. Rudin, Neal Rosen, Elisa de Stanchina, Gary A. Ulaner, Junji Tsurutani, Ronglai Shen, John T. Poirier, Mark G. Kris, Maria E. Arcila, Pedram Razavi, Jorge S. Reis-Filho, Vicky Makker, Alan L. Ho, Darren J. Buonocore, Jason S. Lewis, David M. Hyman, Fabiola Cecchi, Anuja Bhalkikar, Wei-Li Liao, Sheeno Thyparambil, Helena A. Yu, David R. Jones, James M. Isbell, Michael Offin, Tony Ng, Paul R. Barber, Michael F. Berger, David B. Solit, Nancy U. Lin, Rachel A. Freedman, Irmina Diala, Alshad S. Lalani, Clare J. Wilhem, Gregory Weitsman, Besnik Qeriqi, Megan Little, Inna Khodos, Marissa Mattar, Chongrui Xu, Mackenzie L. Myers, Hai-Yan Tu, Sophie Shifman, Yanyan Cai, Laura Baldino, Emiliano Cocco, Sandra Misale, Flavia Michelini, and Bob T. Li

Abstract

Supplementary Table 1

Published
2023
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7. Supplementary Fig 4 from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Author

Maurizio Scaltriti, Charles M. Rudin, Neal Rosen, Elisa de Stanchina, Gary A. Ulaner, Junji Tsurutani, Ronglai Shen, John T. Poirier, Mark G. Kris, Maria E. Arcila, Pedram Razavi, Jorge S. Reis-Filho, Vicky Makker, Alan L. Ho, Darren J. Buonocore, Jason S. Lewis, David M. Hyman, Fabiola Cecchi, Anuja Bhalkikar, Wei-Li Liao, Sheeno Thyparambil, Helena A. Yu, David R. Jones, James M. Isbell, Michael Offin, Tony Ng, Paul R. Barber, Michael F. Berger, David B. Solit, Nancy U. Lin, Rachel A. Freedman, Irmina Diala, Alshad S. Lalani, Clare J. Wilhem, Gregory Weitsman, Besnik Qeriqi, Megan Little, Inna Khodos, Marissa Mattar, Chongrui Xu, Mackenzie L. Myers, Hai-Yan Tu, Sophie Shifman, Yanyan Cai, Laura Baldino, Emiliano Cocco, Sandra Misale, Flavia Michelini, and Bob T. Li

Abstract

Supplementary Fig 4

Published
2023
Full Text
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8. HER2-mediated internalization of cytotoxic agents in ERBB2 amplified or mutant lung cancers

Author

M. Offin, Yanyan Cai, Pedram Razavi, Emiliano Cocco, Alan L. Ho, Maria E. Arcila, Mark G. Kris, Fabiola Cecchi, Clare J. Wilhem, Ronglai Shen, Sheeno Thyparambil, Gregory Weitsman, David R. Jones, Neal Rosen, Charles M. Rudin, Junji Tsurutani, Anuja Bhalkikar, Nan Lin, Darren J. Buonocore, Sophie Shifman, Vicky Makker, Bob T. Li, Michael F. Berger, Elisa de Stanchina, Helena A. Yu, Jason S. Lewis, David B. Solit, Gary A. Ulaner, Marissa Mattar, Maurizio Scaltriti, Megan Little, James M. Isbell, Laura Baldino, Rachel A. Freedman, Sandra Misale, Mackenzie L. Myers, Chongrui Xu, Paul R. Barber, John T. Poirier, Besnik Qeriqi, Hai-Yan Tu, Alshad S. Lalani, Wei-Li Liao, Jorge S. Reis-Filho, David M. Hyman, Inna Khodos, Flavia Michelini, Irmina Diala, and Tony Ng

Subjects
Adult, Male, 0301 basic medicine, Lung Neoplasms, Receptor, ErbB-2, media_common.quotation_subject, Mutant, Endocytosis, Article, 03 medical and health sciences, 0302 clinical medicine, Trastuzumab, Cell Line, Tumor, medicine, Humans, Cytotoxic T cell, Lung cancer, Receptor, Internalization, skin and connective tissue diseases, neoplasms, Aged, media_common, Aged, 80 and over, business.industry, Middle Aged, medicine.disease, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Mutation, Cancer research, Female, business, Tyrosine kinase, medicine.drug
Abstract

Amplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody–drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2-amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy.Significance:T-DM1 is clinically effective in lung cancers with amplification of or mutations in ERBB2. This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy.See related commentary by Rolfo and Russo, p. 643.This article is highlighted in the In This Issue feature, p. 627

Published
2020

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