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Characterization of ALK driven molecular networks identifies perturbed RET and cholinergic signaling in neuroblastoma

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Abstract
Purpose: Activating ALK mutations are present in nearly 10% of primary neuroblastomas and mark patients for treatment with ALK inhibitors. Clinical trials for small molecule ALK inhibitors have been initiated for neuroblastoma and other ALK-driven tumor entities. Recent studies have shown that multiple mechanisms drive resistance to molecular therapies targeting receptor tyrosine kinases including oncogene switching and modulation of various regulatory loops. We anticipated that detailed mapping of the oncogenic ALK-driven signaling in neuroblastoma can pave the way to identify fragile nodes that may serve as additional targets for combination therapies. Experimental design: To achieve this aim, we analysed the transcriptional consequences of mutant ALK signaling in neuroblastoma. As such, we established a 79-gene signature recapitulating the transcriptional response upon ALK inhibition based on transcriptome profiling of ALKwt, ALKF1174L and ALKR1275Q mutant, as well as ALKamplified NB cell lines following ALK inhibition by either NVP-TAE-684, LDK-378, X-396 or Crizotinib. Further, the 79-gene signature was validated in an ALK-inducible NB cell line and primary tumor samples. Results: We established a 79-gene signature marking ALK activity in neuroblastoma cells, which was also preserved to a large extent in other ALK driven tumor entities and across ALKF1174L- and MYCN-driven human and murine NB tumors. Further data mining confirmed that MEK/MAPK, AKT/mTOR and MYC/MYCN pathways are important downstream branches of ALK signaling and highlight a disabled MAPK negative feedback loop. Moreover, using cross-species genomics analysis we show that mutant ALK induces RET and RET driven cholinergic sympathetic neuronal markers such as VIP, VGF, ChAT and VAChT, pointing out to a perturbed RET and cholinergic signaling in neuroblastoma. Conclusions: These novel insights are important leads for further studies exploring novel combination therapy strategies in ALK mutant neuroblastomas and can also pave the way for deeper understanding of the role of ALK signaling in normal sympathetic nervous system development. Moreover, our data emphasize RET as a target for further molecular combination therapies.

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Chicago
Lambertz, Irina, Candy Kumps, Shana Claeys, Sven Lindler, Anneleen Beckers, Els Janssens, Marilena De Mariano, et al. 2014. “Characterization of ALK Driven Molecular Networks Identifies Perturbed RET and Cholinergic Signaling in Neuroblastoma.” In Cancer Pharmacogenomics and Targeted Therapies, 2nd Wellcom Trust Conference, Abstracts.
APA
Lambertz, I., Kumps, C., Claeys, S., Lindler, S., Beckers, A., Janssens, E., De Mariano, M., et al. (2014). Characterization of ALK driven molecular networks identifies perturbed RET and cholinergic signaling in neuroblastoma. Cancer Pharmacogenomics and Targeted Therapies, 2nd Wellcom Trust conference, Abstracts. Presented at the 2nd Wellcom Trust conference on Cancer Pharmacogenomics and Targeted Therapies.
Vancouver
1.
Lambertz I, Kumps C, Claeys S, Lindler S, Beckers A, Janssens E, et al. Characterization of ALK driven molecular networks identifies perturbed RET and cholinergic signaling in neuroblastoma. Cancer Pharmacogenomics and Targeted Therapies, 2nd Wellcom Trust conference, Abstracts. 2014.
MLA
Lambertz, Irina, Candy Kumps, Shana Claeys, et al. “Characterization of ALK Driven Molecular Networks Identifies Perturbed RET and Cholinergic Signaling in Neuroblastoma.” Cancer Pharmacogenomics and Targeted Therapies, 2nd Wellcom Trust Conference, Abstracts. 2014. Print.
@inproceedings{5872705,
  abstract     = {Purpose: Activating ALK mutations are present in nearly 10\% of primary neuroblastomas and mark patients for treatment with ALK inhibitors. Clinical trials for small molecule ALK inhibitors have been initiated for neuroblastoma and other ALK-driven tumor entities. Recent studies have shown that multiple mechanisms drive resistance to molecular therapies targeting receptor tyrosine kinases including oncogene switching and modulation of various regulatory loops. We anticipated that detailed mapping of the oncogenic ALK-driven signaling in neuroblastoma can pave the way to identify fragile nodes that may serve as additional targets for combination therapies. 
Experimental design: To achieve this aim, we analysed the transcriptional consequences of mutant ALK signaling in neuroblastoma. As such, we established a 79-gene signature recapitulating the transcriptional response upon ALK inhibition based on transcriptome profiling of ALKwt, ALKF1174L and  ALKR1275Q mutant,  as well as  ALKamplified NB cell lines following ALK inhibition by either NVP-TAE-684, LDK-378, X-396 or Crizotinib. Further, the 79-gene signature was validated in an ALK-inducible NB cell line and primary tumor samples. 
Results: We established a 79-gene signature marking ALK activity in neuroblastoma cells, which was also preserved to a large extent in other ALK driven tumor entities and across ALKF1174L- and MYCN-driven human and murine NB tumors. Further data mining confirmed that MEK/MAPK, AKT/mTOR and MYC/MYCN pathways are important downstream branches of ALK signaling and highlight a disabled MAPK negative feedback loop. Moreover, using cross-species genomics analysis we show that mutant ALK induces RET and RET driven cholinergic sympathetic neuronal markers such as VIP, VGF, ChAT and VAChT, pointing out to a perturbed RET and cholinergic signaling in neuroblastoma. 
Conclusions: These novel insights are important leads for further studies exploring novel combination therapy strategies in ALK mutant neuroblastomas and can also pave the way for deeper understanding of the role of ALK signaling in normal sympathetic nervous system development. Moreover, our data emphasize RET as a target for further molecular combination therapies.},
  author       = {Lambertz, Irina and Kumps, Candy and Claeys, Shana and Lindler, Sven and Beckers, Anneleen and Janssens, Els and De Mariano, Marilena and De Brouwer, Sara and Gibbons, Jay and Laureys, Genevieve and Porcu, Michael and Van Goethem, Alan and Van Maerken, Tom and Van Roy, Nadine and Zabrocki, Piotr and Cools, Jan and Schulte, Johannes and Vialard, Jorge and Speleman, Franki and De Preter, Katleen},
  booktitle    = {Cancer Pharmacogenomics and Targeted Therapies, 2nd Wellcom Trust conference, Abstracts},
  language     = {eng},
  location     = {Cambridge, UK},
  title        = {Characterization of ALK driven molecular networks identifies perturbed RET and cholinergic signaling in neuroblastoma},
  year         = {2014},
}