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Circulating tumor DNA reveals mechanisms of lorlatinib resistance in patients with relapsed/refractory ALK-driven neuroblastoma

Author

Listed:
  • Esther R. Berko

    (Children’s Hospital of Philadelphia
    Faculty of Medicine)

  • Gabriela M. Witek

    (Children’s Hospital of Philadelphia
    Perelman School of Medicine at the University of Pennsylvania
    University of Pennsylvania)

  • Smita Matkar

    (Children’s Hospital of Philadelphia)

  • Zaritza O. Petrova

    (Yale University School of Medicine
    Yale University)

  • Megan A. Wu

    (Yale University School of Medicine
    Yale University)

  • Courtney M. Smith

    (Yale University School of Medicine
    Yale University)

  • Alex Daniels

    (Children’s Hospital of Philadelphia)

  • Joshua Kalna

    (Children’s Hospital of Philadelphia)

  • Annie Kennedy

    (Children’s Hospital of Philadelphia)

  • Ivan Gostuski

    (University of Pennsylvania)

  • Colleen Casey

    (Children’s Hospital of Philadelphia)

  • Kateryna Krytska

    (Children’s Hospital of Philadelphia)

  • Mark Gerelus

    (Children’s Hospital of Philadelphia)

  • Dean Pavlick

    (Foundation Medicine, Inc)

  • Susan Ghazarian

    (Children’s Hospital Los Angeles
    University of Southern California)

  • Julie R. Park

    (St. Jude Children’s Research Hospital)

  • Araz Marachelian

    (Children’s Hospital Los Angeles
    University of Southern California)

  • John M. Maris

    (Children’s Hospital of Philadelphia
    Perelman School of Medicine at the University of Pennsylvania)

  • Kelly C. Goldsmith

    (Children’s Healthcare of Atlanta
    Emory University School of Medicine
    Seattle Children’s Hospital)

  • Ravi Radhakrishnan

    (University of Pennsylvania
    University of Pennsylvania)

  • Mark A. Lemmon

    (Yale University School of Medicine
    Yale University)

  • Yaël P. Mossé

    (Children’s Hospital of Philadelphia
    Perelman School of Medicine at the University of Pennsylvania)

Abstract

Activating point mutations in Anaplastic Lymphoma Kinase (ALK) have positioned ALK as the only mutated oncogene tractable for targeted therapy in neuroblastoma. Cells with these mutations respond to lorlatinib in pre-clinical studies, providing the rationale for a first-in-child Phase 1 trial (NCT03107988) in patients with ALK-driven neuroblastoma. To track evolutionary dynamics and heterogeneity of tumors, and to detect early emergence of lorlatinib resistance, we collected serial circulating tumor DNA samples from patients enrolled on this trial. Here we report the discovery of off-target resistance mutations in 11 patients (27%), predominantly in the RAS-MAPK pathway. We also identify newly acquired secondary compound ALK mutations in 6 (15%) patients, all acquired at disease progression. Functional cellular and biochemical assays and computational studies elucidate lorlatinib resistance mechanisms. Our results establish the clinical utility of serial circulating tumor DNA sampling to track response and progression and to discover acquired resistance mechanisms that can be leveraged to develop therapeutic strategies to overcome lorlatinib resistance.

Suggested Citation

  • Esther R. Berko & Gabriela M. Witek & Smita Matkar & Zaritza O. Petrova & Megan A. Wu & Courtney M. Smith & Alex Daniels & Joshua Kalna & Annie Kennedy & Ivan Gostuski & Colleen Casey & Kateryna Kryts, 2023. "Circulating tumor DNA reveals mechanisms of lorlatinib resistance in patients with relapsed/refractory ALK-driven neuroblastoma," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38195-0
    DOI: 10.1038/s41467-023-38195-0
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    References listed on IDEAS

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    1. Rani E. George & Takaomi Sanda & Megan Hanna & Stefan Fröhling & William Luther II & Jianming Zhang & Yebin Ahn & Wenjun Zhou & Wendy B. London & Patrick McGrady & Liquan Xue & Sergey Zozulya & Vlad E, 2008. "Activating mutations in ALK provide a therapeutic target in neuroblastoma," Nature, Nature, vol. 455(7215), pages 975-978, October.
    2. Yaël P. Mossé & Marci Laudenslager & Luca Longo & Kristina A. Cole & Andrew Wood & Edward F. Attiyeh & Michael J. Laquaglia & Rachel Sennett & Jill E. Lynch & Patrizia Perri & Geneviève Laureys & Fran, 2008. "Identification of ALK as a major familial neuroblastoma predisposition gene," Nature, Nature, vol. 455(7215), pages 930-935, October.
    3. Yuyan Chen & Junko Takita & Young Lim Choi & Motohiro Kato & Miki Ohira & Masashi Sanada & Lili Wang & Manabu Soda & Akira Kikuchi & Takashi Igarashi & Akira Nakagawara & Yasuhide Hayashi & Hiroyuki M, 2008. "Oncogenic mutations of ALK kinase in neuroblastoma," Nature, Nature, vol. 455(7215), pages 971-974, October.
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    Cited by:

    1. Perla Pucci & Liam C. Lee & Miaojun Han & Jamie D. Matthews & Leila Jahangiri & Michaela Schlederer & Eleanor Manners & Annabel Sorby-Adams & Joshua Kaggie & Ricky M. Trigg & Christopher Steel & Lucy , 2024. "Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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