Editors' ChoiceCancer

A New Kid on the Block

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Science Translational Medicine  11 Dec 2013:
Vol. 5, Issue 215, pp. 215ec205
DOI: 10.1126/scitranslmed.3008080

The identification of biologically and functionally relevant oncogenic mutations and translocations has ushered in a new era of precision cancer therapies directed at inhibiting these drivers of disease development and progression. These successes are best exemplified by drugs such as Gleevec for the treatment of BCR-ABL-driven chronic myelogenous leukemia and anti–epidermal growth factor receptor (EGFR)–based therapies used in the management of lung cancers harboring EGFR mutations. Yet, these therapies benefit only a fraction of cancer patients who harbor these specific genomic alterations. Thus, the identification of additional disease drivers could allow for the development of entirely new classes of drugs.

With this goal in mind, Vaishnavi and colleagues applied targeted next-generation DNA sequencing to patient-derived lung adenocarcinoma samples, with no identifiable genetic alterations by standard clinical assays. They identified and validated in-frame gene fusions involving the kinase domain of the NTRK1 gene. These gene fusions were tumor-specific and could be detected by using fluorescence in situ hybridization in primary patient-derived tumor samples. Biological studies in both cell culture and tumor xenograft mouse models confirmed that these gene fusions resulted in the production of oncogenic proteins that drove increased cellular proliferation, survival, and in vivo tumorigenicity. Using a series of high-affinity nerve growth factor receptor (TRK) inhibitors (ARRY-470 and CEP-701), the authors were able to demonstrate both growth inhibition of tumor cells expressing TRK fusion proteins and modest activity in a single index patient harboring this fusion. This work illustrates the entire spectrum of translational research, from the initial identification of new genetic drivers of cancer development and progression by using next-generation sequencing to the therapeutic modulation of these pathways by using small molecule–based therapies for the treatment of human cancer.

A. Vaishnavi et al., Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med. 19, 1469–1472 (2013). [PubMed]

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