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Epithelial-to-Mesenchymal Transition Is a Mechanism of ALK Inhibitor Resistance in Lung Cancer Independent of ALK Mutation Status.
- Source :
-
Cancer research [Cancer Res] 2019 Apr 01; Vol. 79 (7), pp. 1658-1670. Date of Electronic Publication: 2019 Feb 08. - Publication Year :
- 2019
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Abstract
- Mutations in the ALK gene are detectable in approximately 40% of ALK -rearranged lung cancers resistant to ALK inhibitors. Although epithelial-to-mesenchymal transition (EMT) is a mechanism of resistance to various targeted drugs, its involvement in ALK inhibitor resistance is largely unknown. In this study, we report that both ALK -mutant L1196M and EMT were concomitantly detected in a single crizotinib-resistant lesion in a patient with ALK -rearranged lung cancer. Digital PCR analyses combined with microdissection after IHC staining for EMT markers revealed that ALK L1196M was predominantly detected in epithelial-type tumor cells, indicating that mesenchymal phenotype and ALK mutation can coexist as independent mechanisms underlying ALK inhibitor-resistant cancers. Preclinical experiments with crizotinib-resistant lung cancer cells showed that EMT associated with decreased expression of miR-200c and increased expression of ZEB1 caused cross-resistance to new-generation ALK inhibitors alectinib, ceritinib, and lorlatinib. Pretreatment with the histone deacetylase (HDAC) inhibitor quisinostat overcame this resistance by reverting EMT in vitro and in vivo . These findings indicate that HDAC inhibitor pretreatment followed by a new ALK inhibitor may be useful to circumvent resistance constituted by coexistence of resistance mutations and EMT in the heterogeneous tumor. SIGNIFICANCE: These findings show that dual inhibition of HDAC and ALK receptor tyrosine kinase activities provides a means to circumvent crizotinib resistance in lung cancer.<br /> (©2019 American Association for Cancer Research.)
- Subjects :
- Carbazoles pharmacology
Carcinoma, Non-Small-Cell Lung enzymology
Carcinoma, Non-Small-Cell Lung pathology
Cell Line, Tumor
Crizotinib pharmacology
Drug Resistance, Neoplasm
Histone Deacetylase Inhibitors pharmacology
Humans
Hydroxamic Acids pharmacology
Lung Neoplasms enzymology
MicroRNAs genetics
Piperidines pharmacology
Anaplastic Lymphoma Kinase antagonists & inhibitors
Anaplastic Lymphoma Kinase genetics
Epithelial-Mesenchymal Transition drug effects
Lung Neoplasms pathology
Mutation
Protein Kinase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 79
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 30737231
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-18-2052