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Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors

Author

Listed:
  • Yong Jia

    (Genomics Institute of the Novartis Research Foundation)

  • Cai-Hong Yun

    (Dana-Farber Cancer Institute
    Harvard Medical School
    †Present address: Peking University Institute of Systems Biomedicine and Department of Biophysics, Peking University Health Science Center, Beijing 100191, China.)

  • Eunyoung Park

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Dalia Ercan

    (Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute)

  • Mari Manuia

    (Genomics Institute of the Novartis Research Foundation)

  • Jose Juarez

    (Genomics Institute of the Novartis Research Foundation)

  • Chunxiao Xu

    (Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute)

  • Kevin Rhee

    (Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute)

  • Ting Chen

    (Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute)

  • Haikuo Zhang

    (Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute)

  • Sangeetha Palakurthi

    (Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute)

  • Jaebong Jang

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Gerald Lelais

    (Genomics Institute of the Novartis Research Foundation)

  • Michael DiDonato

    (Genomics Institute of the Novartis Research Foundation)

  • Badry Bursulaya

    (Genomics Institute of the Novartis Research Foundation)

  • Pierre-Yves Michellys

    (Genomics Institute of the Novartis Research Foundation)

  • Robert Epple

    (Genomics Institute of the Novartis Research Foundation)

  • Thomas H. Marsilje

    (Genomics Institute of the Novartis Research Foundation)

  • Matthew McNeill

    (Genomics Institute of the Novartis Research Foundation)

  • Wenshuo Lu

    (Genomics Institute of the Novartis Research Foundation)

  • Jennifer Harris

    (Genomics Institute of the Novartis Research Foundation)

  • Steven Bender

    (Genomics Institute of the Novartis Research Foundation)

  • Kwok-Kin Wong

    (Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute
    Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute)

  • Pasi A. Jänne

    (Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute
    Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute)

  • Michael J. Eck

    (Dana-Farber Cancer Institute
    Harvard Medical School)

Abstract

An allosteric inhibitor, EAI045, is reported that is selective for certain drug-resistant EGFR mutants, but spares the wild-type receptor; combination therapy of EAI045 with EGFR-dimerization-blocking antibodies is effective in mouse models of lung cancer driven by mutant versions of EGFR that are resistant to all previously developed inhibitors.

Suggested Citation

  • Yong Jia & Cai-Hong Yun & Eunyoung Park & Dalia Ercan & Mari Manuia & Jose Juarez & Chunxiao Xu & Kevin Rhee & Ting Chen & Haikuo Zhang & Sangeetha Palakurthi & Jaebong Jang & Gerald Lelais & Michael , 2016. "Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors," Nature, Nature, vol. 534(7605), pages 129-132, June.
    • Handle: RePEc:nat:nature:v:534:y:2016:i:7605:d:10.1038_nature17960
    DOI: 10.1038/nature17960
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    Cited by:

    1. Tyler S. Beyett & Ciric To & David E. Heppner & Jaimin K. Rana & Anna M. Schmoker & Jaebong Jang & Dries J. H. Clercq & Gabriel Gomez & David A. Scott & Nathanael S. Gray & Pasi A. Jänne & Michael J. , 2022. "Molecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Shen Zhao & Wu Zhuang & Baohui Han & Zhengbo Song & Wei Guo & Feng Luo & Lin Wu & Yi Hu & Huijuan Wang & Xiaorong Dong & Da Jiang & Mingxia Wang & Liyun Miao & Qian Wang & Junping Zhang & Zhenming Fu , 2023. "Phase 1b trial of anti-EGFR antibody JMT101 and Osimertinib in EGFR exon 20 insertion-positive non-small-cell lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Erik B. Faber & Luxin Sun & Jian Tang & Emily Roberts & Sornakala Ganeshkumar & Nan Wang & Damien Rasmussen & Abir Majumdar & Laura E. Hirsch & Kristen John & An Yang & Hira Khalid & Jon E. Hawkinson , 2023. "Development of allosteric and selective CDK2 inhibitors for contraception with negative cooperativity to cyclin binding," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. R. Sumanth Iyer & Sarah R. Needham & Ioannis Galdadas & Benjamin M. Davis & Selene K. Roberts & Rico C. H. Man & Laura C. Zanetti-Domingues & David T. Clarke & Gilbert O. Fruhwirth & Peter J. Parker &, 2024. "Drug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    5. Mengmeng Niu & Jing Xu & Yang Liu & Yuhuang Li & Tao He & Liangping Ding & Yajun He & Yong Yi & Fengtian Li & Rongtian Guo & Ya Gao & Rui Li & Luping Li & Mengyuan Fu & Qingyong Hu & Yangkun Luo & Chu, 2021. "FBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth," Nature Communications, Nature, vol. 12(1), pages 1-15, December.

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