ALK inhibitor resistance in ALK(F1174L)-driven neuroblastoma is associated with AXL activation and induction of EMT

Autor: Nathanael S. Gray, David Debruyne, Namrata Bhatnagar, Nathan Moore, Rani E. George, Cheung Nk, William Luther, Bandana Sharma
Rok vydání: 2015
Předmět:
0301 basic medicine
Cancer Research
Epithelial-Mesenchymal Transition
medicine.drug_class
Cell Survival
Pyridines
Blotting
Western
Biology
03 medical and health sciences
Neuroblastoma
Growth factor receptor
Crizotinib
Cell Line
Tumor
Proto-Oncogene Proteins
Genetics
medicine
Anaplastic lymphoma kinase
Humans
Anaplastic Lymphoma Kinase
Epithelial–mesenchymal transition
Sulfones
Molecular Biology
Protein Kinase Inhibitors
AXL receptor tyrosine kinase
GAS6
Reverse Transcriptase Polymerase Chain Reaction
Gene Expression Profiling
Receptor Protein-Tyrosine Kinases
Immunohistochemistry
Axl Receptor Tyrosine Kinase
ALK inhibitor
Enzyme Activation
Gene Expression Regulation
Neoplastic
030104 developmental biology
Pyrimidines
Drug Resistance
Neoplasm
Immunology
Mutation
Cancer research
Pyrazoles
RNA Interference
Original Article
Tyrosine kinase
medicine.drug
Zdroj: Oncogene
ISSN: 1476-5594
Popis: The crizotinib-resistant ALK(F1174L) mutation arises de novo in neuroblastoma (NB) and is acquired in ALK translocation-driven cancers, lending impetus to the development of novel anaplastic lymphoma kinase (ALK) inhibitors with different modes of action. The diaminopyrimidine TAE684 and its derivative ceritinib (LDK378), which are structurally distinct from crizotinib, are active against NB cells expressing ALK(F1174L). Here we demonstrate acquired resistance to TAE684 and LDK378 in ALK(F1174L)-driven human NB cells that is linked to overexpression and activation of the AXL tyrosine kinase and epithelial-to-mesenchymal transition (EMT). AXL phosphorylation conferred TAE684 resistance to NB cells through upregulated extracellular signal-regulated kinase (ERK) signaling. Inhibition of AXL partly rescued TAE684 resistance, resensitizing these cells to this compound. AXL activation in resistant cells was mediated through increased expression of the active form of its ligand, GAS6, that also served to stabilize the AXL protein. Although ectopic expression of AXL and TWIST2 individually in TAE684-sensitive parental cells led to the elevated expression of mesenchymal markers and invasive capacity, only AXL overexpression induced resistance to TAE684 as well. TAE684-resistant cells showed greater sensitivity to HSP90 inhibition than did their parental counterparts, with downregulation of AXL and AXL-mediated ERK signaling. Our studies indicate that aberrant AXL signaling and development of an EMT phenotype underlie resistance of ALK(F1174L)-driven NB cells to TAE684 and its derivatives. We suggest that the combination of ALK and AXL or HSP90 inhibitors be considered to delay the emergence of such resistance.
Databáze: OpenAIRE
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