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HER2 + breast cancers evade anti-HER2 therapy via a switch in driver pathway

Author

Listed:
  • Alison E. Smith

    (Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center
    Weill Cornell Medicine)

  • Emanuela Ferraro

    (Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center
    Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center)

  • Anton Safonov

    (Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center
    Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center)

  • Cristina Bernado Morales

    (Preclinical Research Program, Vall d’Hebron Institute of Oncology)

  • Enrique J. Arenas Lahuerta

    (Preclinical Research Program, Vall d’Hebron Institute of Oncology)

  • Qing Li

    (Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center)

  • Amanda Kulick

    (Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center)

  • Dara Ross

    (Memorial Sloan Kettering Cancer Center)

  • David B. Solit

    (Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center
    Weill Cornell Medicine)

  • Elisa Stanchina

    (Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center)

  • Jorge Reis-Filho

    (Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Neal Rosen

    (Molecular Pharmacology and Chemistry Program and Center for Cell Engineering, Memorial Sloan Kettering Cancer Center)

  • Joaquín Arribas

    (Preclinical Research Program, Vall d’Hebron Institute of Oncology)

  • Pedram Razavi

    (Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center
    Weill Cornell Medicine
    Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center)

  • Sarat Chandarlapaty

    (Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center
    Weill Cornell Medicine
    Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center)

Abstract

Inhibition of HER2 in HER2-amplified breast cancer has been remarkably successful clinically, as demonstrated by the efficacy of HER-kinase inhibitors and HER2-antibody treatments. Whilst resistance to HER2 inhibition is common in the metastatic setting, the specific programs downstream of HER2 driving resistance are not established. Through genomic profiling of 733 HER2-amplified breast cancers, we identify enrichment of somatic alterations that promote MEK/ERK signaling in metastatic tumors with shortened progression-free survival on anti-HER2 therapy. These mutations, including NF1 loss and ERBB2 activating mutations, are sufficient to mediate resistance to FDA-approved HER2 kinase inhibitors including tucatinib and neratinib. Moreover, resistant tumors lose AKT dependence while undergoing a dramatic sensitization to MEK/ERK inhibition. Mechanistically, this driver pathway switch is a result of MEK-dependent activation of CDK2 kinase. These results establish genetic activation of MAPK as a recurrent mechanism of anti-HER2 therapy resistance that may be effectively combated with MEK/ERK inhibitors.

Suggested Citation

  • Alison E. Smith & Emanuela Ferraro & Anton Safonov & Cristina Bernado Morales & Enrique J. Arenas Lahuerta & Qing Li & Amanda Kulick & Dara Ross & David B. Solit & Elisa Stanchina & Jorge Reis-Filho &, 2021. "HER2 + breast cancers evade anti-HER2 therapy via a switch in driver pathway," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27093-y
    DOI: 10.1038/s41467-021-27093-y
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    References listed on IDEAS

    as
    1. René H. Medema & Geert J. P. L. Kops & Johannes L. Bos & Boudewijn M. T. Burgering, 2000. "AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1," Nature, Nature, vol. 404(6779), pages 782-787, April.
    2. David B. Solit & Levi A. Garraway & Christine A. Pratilas & Ayana Sawai & Gad Getz & Andrea Basso & Qing Ye & Jose M. Lobo & Yuhong She & Iman Osman & Todd R. Golub & Judith Sebolt-Leopold & William R, 2006. "BRAF mutation predicts sensitivity to MEK inhibition," Nature, Nature, vol. 439(7074), pages 358-362, January.
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    Cited by:

    1. Min Yan & Limin Niu & Huimin Lv & Mengwei Zhang & Jing Wang & Zhenzhen Liu & Xiuchun Chen & Zhenduo Lu & Chongjian Zhang & Huiai Zeng & Shengnan Zhao & Yajing Feng & Huihui Sun & Huajun Li, 2023. "Dalpiciclib and pyrotinib in women with HER2-positive advanced breast cancer: a single-arm phase II trial," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    2. Smruthy Sivakumar & Dexter X. Jin & Hanna Tukachinsky & Karthikeyan Murugesan & Kimberly McGregor & Natalie Danziger & Dean Pavlick & Ole Gjoerup & Jeffrey S. Ross & Robert Harmon & Jon Chung & Brenna, 2022. "Tissue and liquid biopsy profiling reveal convergent tumor evolution and therapy evasion in breast cancer," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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