IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-38195-0.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-38195-0
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-38195-0?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. Isabelle Janoueix-Lerosey & Delphine Lequin & Laurence Brugières & Agnès Ribeiro & Loïc de Pontual & Valérie Combaret & Virginie Raynal & Alain Puisieux & Gudrun Schleiermacher & Gaëlle Pierron & Domi, 2008. "Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma," Nature, Nature, vol. 455(7215), pages 967-970, October.
    3. Christopher Abbosh & Nicolai J. Birkbak & Gareth A. Wilson & Mariam Jamal-Hanjani & Tudor Constantin & Raheleh Salari & John Le Quesne & David A. Moore & Selvaraju Veeriah & Rachel Rosenthal & Teresa , 2017. "Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution," Nature, Nature, vol. 545(7655), pages 446-451, May.
    4. 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.
    5. 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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Cécile Thirant & Agathe Peltier & Simon Durand & Amira Kramdi & Caroline Louis-Brennetot & Cécile Pierre-Eugène & Margot Gautier & Ana Costa & Amandine Grelier & Sakina Zaïdi & Nadège Gruel & Irène Ji, 2023. "Reversible transitions between noradrenergic and mesenchymal tumor identities define cell plasticity in neuroblastoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Tas ML & Van Noesel MM & Van den Boogaard ML & Schild GG & Hehir-Kwa JY & Molenaar JJ & Van Noesel MM & Van de Sande MAJ & Van de Sande MAJ & Bovée JVMG & Flucke UE & Flucke UE & Koster J, 2020. "ZFP42: A New Tumor Predisposition Gene? Presentation of a Patient with two Neoplasms in Childhood," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 27(5), pages 21166-21172, May.
    3. Karin Schmelz & Joern Toedling & Matt Huska & Maja C. Cwikla & Louisa-Marie Kruetzfeldt & Jutta Proba & Peter F. Ambros & Inge M. Ambros & Sengül Boral & Marco Lodrini & Celine Y. Chen & Martin Burker, 2021. "Spatial and temporal intratumour heterogeneity has potential consequences for single biopsy-based neuroblastoma treatment decisions," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    4. Bieke Decaesteker & Amber Louwagie & Siebe Loontiens & Fanny De Vloed & Sarah-Lee Bekaert & Juliette Roels & Suzanne Vanhauwaert & Sara De Brouwer & Ellen Sanders & Alla Berezovskaya & Geertrui Deneck, 2023. "SOX11 regulates SWI/SNF complex components as member of the adrenergic neuroblastoma core regulatory circuitry," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Mingyun Bae & Gyuhee Kim & Tae-Rim Lee & Jin Mo Ahn & Hyunwook Park & Sook Ryun Park & Ki Byung Song & Eunsung Jun & Dongryul Oh & Jeong-Won Lee & Young Sik Park & Ki-Won Song & Jeong-Sik Byeon & Bo H, 2023. "Integrative modeling of tumor genomes and epigenomes for enhanced cancer diagnosis by cell-free DNA," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    6. Bin Qiu & Wei Guo & Fan Zhang & Fang Lv & Ying Ji & Yue Peng & Xiaoxi Chen & Hua Bao & Yang Xu & Yang Shao & Fengwei Tan & Qi Xue & Shugeng Gao & Jie He, 2021. "Dynamic recurrence risk and adjuvant chemotherapy benefit prediction by ctDNA in resected NSCLC," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    7. Nicolette M. Fonseca & Corinne Maurice-Dror & Cameron Herberts & Wilson Tu & William Fan & Andrew J. Murtha & Catarina Kollmannsberger & Edmond M. Kwan & Karan Parekh & Elena Schönlau & Cecily Q. Bern, 2024. "Prediction of plasma ctDNA fraction and prognostic implications of liquid biopsy in advanced prostate cancer," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    8. David Hsiehchen & Leslie Bucheit & Dong Yang & Muhammad Shaalan Beg & Mir Lim & Sunyoung S. Lee & Pashtoon Murtaza Kasi & Ahmed O. Kaseb & Hao Zhu, 2022. "Genetic features and therapeutic relevance of emergent circulating tumor DNA alterations in refractory non-colorectal gastrointestinal cancers," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    9. Dan Daniel Erdmann-Pham & Sanjit Singh Batra & Timothy K. Turkalo & James Durbin & Marco Blanchette & Iwei Yeh & Hunter Shain & Boris C. Bastian & Yun S. Song & Daniel S. Rokhsar & Dirk Hockemeyer, 2023. "Tracing cancer evolution and heterogeneity using Hi-C," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    10. Yi Zhou & Peng Ke & Xiaoyan Bao & Honghui Wu & Yiyi Xia & Zhentao Zhang & Haiqing Zhong & Qi Dai & Linjie Wu & Tiantian Wang & Mengting Lin & Yaosheng Li & Xinchi Jiang & Qiyao Yang & Yiying Lu & Xinc, 2022. "Peptide nano-blanket impedes fibroblasts activation and subsequent formation of pre-metastatic niche," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38195-0. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.