Cancer Res
School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
Published: December 2018
: Targeted therapy changed the standard of care in ALK-dependent tumors. However, resistance remains a major challenge. Lorlatinib is a third-generation ALK inhibitor that inhibits most ALK mutants resistant to current ALK inhibitors. In this study, we utilize lorlatinib-resistant anaplastic large cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), and neuroblastoma cell lines and to investigate the acquisition of resistance and its underlying mechanisms. ALCL cells acquired compound ALK mutations G1202R/G1269A and C1156F/L1198F at high drug concentrations. ALCL xenografts selected showed recurrent N1178H (5/10 mice) and G1269A (4/10 mice) mutations. Interestingly, intracellular localization of NPM/ALKN skewed toward the cytoplasm in human cells, possibly mimicking overexpression. RNA sequencing of resistant cells showed significant alteration of PI3K/AKT and RAS/MAPK pathways. Functional validation by small-molecule inhibitors confirmed the involvement of these pathways in resistance to lorlatinib. NSCLC cells exposed to lorlatinib acquired hyperactivation of EGFR, which was blocked by erlotinib to restore sensitivity to lorlatinib. In neuroblastoma, whole-exome sequencing and proteomic profiling of lorlatinib-resistant cells revealed a truncating NF1 mutation and hyperactivation of EGFR and ErbB4. These data provide an extensive characterization of resistance mechanisms that may arise in different ALK-positive cancers following lorlatinib treatment. SIGNIFICANCE: High-throughput genomic, transcriptomic, and proteomic profiling reveals various mechanisms by which multiple tumor types acquire resistance to the third-generation ALK inhibitor lorlatinib.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1158/0008-5472.CAN-18-1867 | DOI Listing |
Front Pharmacol
December 2024
Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Cell Death Dis
December 2024
Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
The fusion event between EML4 and ALK drives a significant oncogenic activity in 5% of non-small cell lung cancer (NSCLC). Even though potent ALK-tyrosine kinase inhibitors (ALK-TKIs) are successfully used for the treatment of EML4-ALK-positive NSCLC patients, a subset of those patients eventually acquire resistance during their therapy. Here, we investigate the kinase responses in EML4-ALK V1 and V3-harbouring NSCLC cancer cells after acute inhibition with ALK TKI, lorlatinib (LOR).
View Article and Find Full Text PDFCancer Chemother Pharmacol
December 2024
Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford Cancer Institute, Stanford, USA.
Progressive leptomeningeal metastases (LM) are associated with intractable neurological symptoms and a poor prognosis, and effective treatment options are limited. Intrathecal (IT) pemetrexed has been shown to confer clinical benefit in lung adenocarcinoma, yet our understanding of the efficacy and safety of the treatment is limited. We report a patient with a long-standing history of leptomeningeal disease due to ALK-positive adenocarcinoma of the lung, previously controlled by increased doses of lorlatinib (125 mg/day).
View Article and Find Full Text PDFCureus
November 2024
Hematology and Medical Oncology, Tripler Army Medical Center, Honolulu, USA.
The anaplastic lymphoma kinase (ALK) gene plays crucial roles in both normal brain development and oncogenesis, particularly in non-small cell lung cancer (NSCLC). Metastatic ALK-positive NSCLC is characterized by ALK tyrosine kinase domain rearrangements, prompting the use of ALK tyrosine kinase inhibitors (TKIs) to target the mutation. While first-line treatment options include alectinib, brigatinib, and lorlatinib per National Comprehensive Cancer Network (NCCN) guidelines, therapeutic challenges arise in cases of disease progression.
View Article and Find Full Text PDFTransl Lung Cancer Res
November 2024
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Background: Rearrangement in anaplastic lymphoma kinase () occurs in 4-7% of non-small cell lung cancer (NSCLC) cases. Despite improved survival with tyrosine kinase inhibitors (TKIs), treatment resistance remains challenging. This retrospective study analyzed advanced ALK-positive NSCLC patients, focusing on clinical aspects, treatments, resistance, and outcomes.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!
© LitMetric 2025. All rights reserved.