PDGFR blockade is a rational and effective therapy for NPM-ALK-driven lymphomas.

1] Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria. [2].
Nature medicine (Impact Factor: 28.05). 10/2012; DOI: 10.1038/nm.2966
Source: PubMed

ABSTRACT Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin's lymphoma found in children and young adults. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK-triggered lymphoma growth have been only partly unveiled. Here we show that the activator protein 1 family members JUN and JUNB promote lymphoma development and tumor dissemination through transcriptional regulation of platelet-derived growth factor receptor-β (PDGFRB) in a mouse model of NPM-ALK-triggered lymphomagenesis. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor in transplanted NPM-ALK tumors. Notably, inhibition of PDGFRA and PDGFRB in a patient with refractory late-stage NPM-ALK(+) ALCL resulted in rapid, complete and sustained remission. Together, our data identify PDGFRB as a previously unknown JUN and JUNB target that could be a highly effective therapy for ALCL.

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    ABSTRACT: Rearrangements involving the Anaplastic Lymphoma Kinase (ALK) gene are defining events in several tumors, including Anaplastic Large Cell Lymphoma (ALCL) and Non-Small Cell Lung Carcinoma (NSCLC). In such cancers, the oncogenic activity of ALK stimulates signaling pathways that induce cell transformation and promote tumor growth. In search for common pathways activated by oncogenic ALK across different tumors types, we found that hypoxia pathways were significantly enriched in ALK-rearranged ALCL and NSCLC, as compared to other types of T cell lymphoma or EGFR and K-RAS mutated NSCLC, respectively. Consistently, in both ALCL and NSCLC we found that under hypoxic conditions ALK directly regulated the abundance of Hypoxia-Inducible Factors (HIFs), which are key players of the hypoxia response in normal tissues and cancers. In ALCL, the upregulation of HIF-1α and HIF-2α in hypoxic conditions required ALK activity and its downstream signaling proteins Stat3 and C/EBPβ. In vivo, ALK regulated VEGFA production and tumor angiogenesis in ALCL and NSCLC, and the treatment with the anti-VEGFA antibody bevacizumab strongly impaired ALCL growth in mouse xenografts. Finally, HIF-2α, but not HIF-1α, was required for ALCL growth in vivo whereas the growth and metastasis potential of ALK-rearranged NSCLC required both HIF-1α and HIF-2α. In conclusion, we uncovered an ALK specific regulation of the hypoxia response across different ALK positive tumor types, and propose HIFs as a powerful specific therapeutic target in ALK-rearranged ALCL and NSCLC.
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May 22, 2014

Daniela Laimer