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

• Type of Material: Article
• Authors: Esther R Berko, Childrens Hospital of Philadelphia; Gabriela M Witek, Childrens Hospital of Philadelphia; Smita Matkar, Childrens Hospital of Philadelphia; Zaritza O Petrova, Yale University; Megan A Wu, Yale University; Courtney M Smith, Yale University; Alex Daniels, Childrens Hospital of Philadelphia; Joshua Kalna, Childrens Hospital of Philadelphia; Annie Kennedy, Childrens Hospital of Philadelphia; Ivan Gostuski, University of Pennsylvania; Colleen Casey, Childrens Hospital of Philadelphia; Kateryna Krytska, Childrens Hospital of Philadelphia; Mark Gerelus, Childrens Hospital of Philadelphia; Dean Pavlick, Foundation Medicine, Inc, Cambridge; Susan Ghazarian, Children’s Hospital Los Angeles; Julie R Park, St. Jude Children’s Research Hospital, Memphis; Araz Marachelian, Children’s Hospital Los Angeles; John M Maris, Childrens Hospital of Philadelphia; Kelly Goldsmith, Emory University; Ravi Radhakrishnan, University of Pennsylvania; Mark A Lemmon, Yale University; Yaël P. Mosse, Childrens Hospital of Philadelphia
• Language: English
• Date: 2023-05-05
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-023-38195-0
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 14
• Issue: 1
• Start Page: 2601
• End Page: 2601
• Keywords: KINASE; RECEPTOR; LUNG-CANCER; Multidisciplinary Sciences; ACCURATE DOCKING; CRIZOTINIB; Science & Technology - Other Topics; TARGETING ALK; LARGE-CELL LYMPHOMA; ACTIVATING MUTATIONS; Science & Technology; INHIBITOR PF-06463922; MOLECULAR-DYNAMICS
• Research Categories: Health Sciences, Oncology; Health Sciences, Pharmacology

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.