Editors' ChoiceCancer Therapy

Oncogene Addiction: How Cells Handle the Habit

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Science Translational Medicine  08 Jan 2014:
Vol. 6, Issue 218, pp. 218ec5
DOI: 10.1126/scitranslmed.3008243

The oncogenic BCR-ABL kinase of chronic myelogenous leukemia (CML) helped define the paradigm for oncogene addiction. Block the mutant kinase in cancer cells, and you break their signaling habit. Using tyrosine kinase inhibitors, clinicians have been able to achieve control of CML, and this approach has been successfully applied to other cancers—BRAF mutant melanoma, for example. Now, Asmussen et al. explore the nature of oncogene addition in CML and describe a negative feedback loop that may explain why these cells can’t easily kick the BCR-ABL habit.

The authors began with the observation that transient exposure to tyrosine kinase inhibitors commits CML cells to apoptosis, suggesting a durable alteration in protein signaling that persists even after the drug wears off. Beginning with an unbiased screen of altered phophoproteins, the authors found that growth factor (GF) signaling is key to this process. They then made use of the human erytholeukemia cell line TF1, which can be rendered GF-independent through transduction with the BCR-ABL oncogene. In isogenic TF1 cells, BCR-ABL generated persistent inhibition of GF signaling, reinforcing the oncogene addiction. Additional experiments demonstrated that this MEK-dependent inhibition appears to cinch the deal on tyrosine kinase inhibitor–mediated apoptosis by eliminating the ability of GF signaling to rescue cells. Last, the authors compared the negative feedback loop generated by BCR-ABL with that of BRAFV600E or FLT4-ITD. They found that each oncogene has a distinct feedback signature, both in magnitude and duration.

Asmussen et al. make a compelling argument that a fortuitous combination of aberrant oncogene signaling and altered negative feedback makes BCR-ABL inhibition a particularly potent therapeutic approach. Differences in GF inhibition between oncogenes may be an important variable in the further development of targeted inhibitors.

J. Asmussen et al., MEK-dependent negative feedback underlies BCR-ABL-mediated oncogene addiction. Cancer Discovery, published online 20 December 2013 (10.1158/2159-8290.CD-13-0235). [Abstract]

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