Osimertinib Overcomes Alectinib Resistance Caused by Amphiregulin in a Leptomeningeal Carcinomatosis Model of ALK-Rearranged Lung Cancer.
Acrylamides
Amphiregulin
/ genetics
Anaplastic Lymphoma Kinase
/ genetics
Aniline Compounds
Animals
Carbazoles
Cell Line, Tumor
Drug Resistance, Neoplasm
ErbB Receptors
/ genetics
Humans
Lung Neoplasms
/ drug therapy
Meningeal Carcinomatosis
Mice
Piperidines
Protein Kinase Inhibitors
/ pharmacology
Receptor Protein-Tyrosine Kinases
/ genetics
Alectinib resistance
EML4-ALK
Leptomeningeal metastasis
Osimertinib
Journal
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
ISSN: 1556-1380
Titre abrégé: J Thorac Oncol
Pays: United States
ID NLM: 101274235
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
09
10
2019
revised:
06
01
2020
accepted:
09
01
2020
pubmed:
24
1
2020
medline:
7
1
2021
entrez:
24
1
2020
Statut:
ppublish
Résumé
Leptomeningeal carcinomatosis (LMC) occurs frequently in anaplastic lymphoma kinase (ALK)-rearranged NSCLC and develops acquired resistance to ALK tyrosine kinase inhibitors (ALK TKIs). This study aimed to clarify the resistance mechanism to alectinib, a second-generation ALK TKI, in LMC and test a novel therapeutic strategy. We induced alectinib resistance in an LMC mouse model with ALK-rearranged NSCLC cell line, A925LPE3, by continuous oral alectinib treatment, established A925L/AR cells. Resistance mechanisms were analyzed using several assays, including Western blot and receptor tyrosine kinase array. We also measured amphiregulin (AREG) concentrations in cerebrospinal fluid from patients with ALK-rearranged NSCLC with alectinib-refractory LMC by enzyme-linked immunosorbent assay. A925L/AR cells were moderately resistant to various ALK TKIs, such as alectinib, crizotinib, ceritinib, and lorlatinib, compared with parental cells in vitro. A925L/AR cells acquired the resistance by EGFR activation resulting from AREG overexpression caused by decreased expression of microRNA-449a. EGFR TKIs and anti-EGFR antibody resensitized A925L/AR cells to alectinib in vitro. In the LMC model with A925L/AR cells, combined treatment with alectinib and EGFR TKIs, such as erlotinib and osimertinib, successfully controlled progression of LMC. Mass spectrometry imaging showed accumulation of the EGFR TKIs in the tumor lesions. Moreover, notably higher AREG levels were detected in cerebrospinal fluid of patients with alectinib-resistant ALK-rearranged NSCLC with LMC (n = 4), compared with patients with EGFR-mutated NSCLC with EGFR TKI-resistant LMC (n = 30), or patients without LMC (n = 24). These findings indicate the potential of novel therapies targeting both ALK and EGFR for the treatment of ALK TKI-resistant LMC in ALK-rearranged NSCLC.
Identifiants
pubmed: 31972351
pii: S1556-0864(20)30022-8
doi: 10.1016/j.jtho.2020.01.001
pii:
doi:
Substances chimiques
Acrylamides
0
Amphiregulin
0
Aniline Compounds
0
Carbazoles
0
Piperidines
0
Protein Kinase Inhibitors
0
osimertinib
3C06JJ0Z2O
Anaplastic Lymphoma Kinase
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
alectinib
LIJ4CT1Z3Y
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
752-765Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.