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

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.

• Authors: 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, Yaël P Mossé
• Journal: Nature communications (Nat Commun) Vol. 14 Issue 1 Pg. 2601 (05 05 2023) ISSN: 2041-1723 [Electronic] England
• PMID: 37147298 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Author(s).

Chemical References

• Aminopyridines
• Anaplastic Lymphoma Kinase
• Circulating Tumor DNA
• Lactams, Macrocyclic
• lorlatinib
• Protein Kinase Inhibitors

Topics

• Humans
• Aminopyridines (therapeutic use)
• Anaplastic Lymphoma Kinase (genetics)
• Carcinoma, Non-Small-Cell Lung (genetics)
• Circulating Tumor DNA (genetics)
• Drug Resistance, Neoplasm (genetics)
• Lactams, Macrocyclic (therapeutic use)
• Lung Neoplasms (genetics)
• Mutation
• Neuroblastoma (drug therapy, genetics)
• Protein Kinase Inhibitors (therapeutic use)