Upregulation of MAPK Negative Feedback Regulators and RET in Mutant ALK Neuroblastoma: Implications for Targeted Treatment

Activating ALK mutations are present in almost 10% of primary neuroblastomas and mark patients for treatment with small-molecule ALK inhibitors in clinical trials. However, recent studies have shown that multiple mechanisms drive resistance to these molecular therapies. We anticipated that detailed...

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Bibliographic Details
Published in:Clinical cancer research 2015-07, Vol.21 (14), p.3327-3339
Main Authors: Lambertz, Irina, Kumps, Candy, Claeys, Shana, Lindner, Sven, Beckers, Anneleen, Janssens, Els, Carter, Daniel R, Cazes, Alex, Cheung, Belamy B, De Mariano, Marilena, De Bondt, An, De Brouwer, Sara, Delattre, Olivier, Gibbons, Jay, Janoueix-Lerosey, Isabelle, Laureys, Geneviève, Liang, Chris, Marchall, Glenn M, Porcu, Michael, Takita, Junko, Trujillo, David Camacho, Van Den Wyngaert, Ilse, Van Roy, Nadine, Van Goethem, Alan, Van Maerken, Tom, Zabrocki, Piotr, Cools, Jan, Schulte, Johannes H, Vialard, Jorge, Speleman, Frank, De Preter, Katleen
Format: Article
Language:English
Subjects:
Alkaline Phosphatase - genetics
Animals
Blotting, Western
Cell Line, Tumor
Drug Resistance, Neoplasm - genetics
Feedback, Physiological
Humans
Mice
Mice, Transgenic
Mitogen-Activated Protein Kinase Kinases - metabolism
Molecular Targeted Therapy - methods
Neuroblastoma - genetics
Neuroblastoma - metabolism
Oligonucleotide Array Sequence Analysis
Polymerase Chain Reaction
Proto-Oncogene Proteins c-ret - metabolism
Transcriptome
Up-Regulation
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Summary:Activating ALK mutations are present in almost 10% of primary neuroblastomas and mark patients for treatment with small-molecule ALK inhibitors in clinical trials. However, recent studies have shown that multiple mechanisms drive resistance to these molecular therapies. We anticipated that detailed mapping of the oncogenic ALK-driven signaling in neuroblastoma can aid to identify potential fragile nodes as additional targets for combination therapies. To achieve this goal, transcriptome profiling was performed in neuroblastoma cell lines with the ALK(F1174L) or ALK(R1275Q) hotspot mutations, ALK amplification, or wild-type ALK following pharmacologic inhibition of ALK using four different compounds. Next, we performed cross-species genomic analyses to identify commonly transcriptionally perturbed genes in MYCN/ALK(F1174L) double transgenic versus MYCN transgenic mouse tumors as compared with the mutant ALK-driven transcriptome in human neuroblastomas. A 77-gene ALK signature was established and successfully validated in primary neuroblastoma samples, in a neuroblastoma cell line with ALK(F1174L) and ALK(R1275Q) regulable overexpression constructs and in other ALKomas. In addition to the previously established PI3K/AKT/mTOR, MAPK/ERK, and MYC/MYCN signaling branches, we identified that mutant ALK drives a strong upregulation of MAPK negative feedback regulators and upregulates RET and RET-driven sympathetic neuronal markers of the cholinergic lineage. We provide important novel insights into the transcriptional consequences and the complexity of mutant ALK signaling in this aggressive pediatric tumor. The negative feedback loop of MAPK pathway inhibitors may affect novel ALK inhibition therapies, whereas mutant ALK induced RET signaling can offer novel opportunities for testing ALK-RET oriented molecular combination therapies.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.ccr-14-2024