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

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 Krytska, Mark Gerelus, Dean Pavlick, Susan Ghazarian, Julie R. Park, Araz Marachelian, John M. Maris, Kelly C. Goldsmith, Ravi Radhakrishnan, Mark A. Lemmon () and Yaël P. Mossé ()
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Esther R. Berko: Children’s Hospital of Philadelphia
Gabriela M. Witek: Children’s Hospital of Philadelphia
Smita Matkar: Children’s Hospital of Philadelphia
Zaritza O. Petrova: Yale University School of Medicine
Megan A. Wu: Yale University School of Medicine
Courtney M. Smith: Yale University School of Medicine
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
Julie R. Park: St. Jude Children’s Research Hospital
Araz Marachelian: Children’s Hospital Los Angeles
John M. Maris: Children’s Hospital of Philadelphia
Kelly C. Goldsmith: Children’s Healthcare of Atlanta
Ravi Radhakrishnan: University of Pennsylvania
Mark A. Lemmon: Yale University School of Medicine
Yaël P. Mossé: Children’s Hospital of Philadelphia

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38195-0

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