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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Circulating tumor DNA reveals mechanisms of lorlatinib resistance in patients with relapsed/refractory ALK-driven
Esther R Berko1,2, Gabriela M Witek1,3,4, Smita Matkar1
1Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
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.
Insights
Targeted therapy for neuroblastoma shows promise, but resistance can emerge. Serial liquid biopsies revealed off-target mutations and new Anaplastic Lymphoma Kinase (ALK) mutations, guiding future treatment strategies.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Activating Anaplastic Lymphoma Kinase (ALK) mutations are key drivers in neuroblastoma.
- Lorlatinib shows preclinical efficacy against ALK-mutated neuroblastoma, prompting clinical trials.
Purpose of the Study:
- To investigate the mechanisms of lorlatinib resistance in pediatric neuroblastoma patients.
- To assess the utility of serial circulating tumor DNA (ctDNA) for monitoring treatment response and resistance evolution.
Main Methods:
- Serial ctDNA sampling from patients in a Phase 1 trial of lorlatinib for ALK-driven neuroblastoma.
- Genomic analysis of ctDNA to identify resistance mutations.
- Functional assays (cellular, biochemical) and computational studies to elucidate resistance mechanisms.
Main Results:
- Off-target resistance mutations, primarily in the RAS-MAPK pathway, were identified in 27% of patients.
- Secondary compound ALK mutations conferring resistance were acquired at disease progression in 15% of patients.
- Mechanisms of lorlatinib resistance were elucidated through functional and computational analyses.
Conclusions:
- Serial ctDNA sampling is a valuable tool for tracking tumor evolution and detecting emergent resistance during targeted therapy.
- Understanding resistance mechanisms, including off-target and secondary ALK mutations, is crucial for developing strategies to overcome lorlatinib resistance in neuroblastoma.
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