Editors' ChoiceCancer

Turning Off the Cancer Switch

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Science Translational Medicine  06 Oct 2010:
Vol. 2, Issue 52, pp. 52ec153
DOI: 10.1126/scitranslmed.3001750

Signaling pathways such as the MAP kinase (MAPK) pathway are often erroneously switched on in cancer. A member of the MAPK family called BMK1 has been implicated in several tumors. Now, Yang et al. report a small-molecule inhibitor that blocks the action of BMK1 and may prove useful as an anticancer drug.

Using a mass spectrometry screen, Yang et al. first determined that BMK1 blocks the action of the tumor suppressor promyelocytic leukemia protein (PML), which normally prevents the proliferation of tumor cells. By phosphorylating PML, BMK1 prevents PML from up-regulating the expression of the p21 gene, which is a master regulator that keeps cell growth in check. Next, in the course of designing small-molecule inhibitors to block a related group of kinases, the authors serendipitously discovered one (XMD8-92) that was particularly potent against BMK1 activity. Treatment of cancer cell lines in vitro with this drug disrupted BMK1 function, boosted expression of p21, and reduced tumor cell proliferation. However, in tumor cells lacking PML expression, the effect of the drug was attenuated. This demonstrates that PML is important for XMD8-92 to be able to decrease cancer cell proliferation.

The authors next tested XMD8-92 in a mouse model of human cancer. They showed that high doses of the drug could be administered without apparent toxicity and that XMD8-92 inhibited growth of the human tumor xenografts. When the authors used RNA interference to suppress PML activity in the human tumor xenografts, they saw that the drug could only partly block tumor growth. This implies that BMK1’s ability to boost tumor growth may occur not only through blocking PML action but also through other avenues. Indeed, XMD8-92 reduced blood vessel formation.

These new findings highlight BMK1 as a new therapeutic target and identify the small-molecule inhibitor XMD8-92 as a safe and effective anticancer agent that may be of value for treating human tumors.

Q. Yang et al., Pharmacological inhibition of BMK1 suppresses tumor growth through promyelocytic leukemia protein. Cancer Cell 18, 258–267 (2010). [Abstract]

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