Research ArticleCancer

Interfering with Resistance to Smoothened Antagonists by Inhibition of the PI3K Pathway in Medulloblastoma

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Science Translational Medicine  29 Sep 2010:
Vol. 2, Issue 51, pp. 51ra70
DOI: 10.1126/scitranslmed.3001599

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An End Run Against Tumor Resistance

Cancer cells are as clever as microbes. Mustering their considerable abilities to rapidly replicate and evolve, both cancer cells and bacteria quickly develop resistance to the drugs we use to fight them. Modern medicine confronts a growing population of pathogens that cannot be treated by our usual antibiotics, and oncologists must be prepared with second- and third-line therapies, because tumors that retreat from initial drug treatments often return with renewed vigor. Buonamici et al. confront this problem in their study of a new class of cancer therapeutic agents now in clinical trials—antagonists of a membrane protein called Smoothened (Smo). The Smo receptor normally regulates a developmental pathway but is abnormally activated in medulloblastoma (a malignant brain tumor) and basal cell carcinoma of the skin. Medulloblastomas in mice respond well to these Smo antagonists but soon become resistant, these authors find. If, however, an inhibitor of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is added to the initial drug cocktail, resistance is delayed or even prevented.

In some cancers, the Smo receptor is active even when its ligand is absent, conferring dependence of the tumor on the downstream Hedgehog signaling pathway, which ultimately regulates gene expression through the Gli transcription factors. Treatment of Smo-addicted tumors in mice with Smo antagonists ultimately leads to development of resistance, although tumor growth is inhibited for a while. The authors found that the tumors eluded the drug in several ways: The genes for the Gli transcription factors were sometimes amplified, compensating for loss of pathway stimulation. In other resistant tumors, there were point mutations in the Smo receptor itself that allowed reactivation of the pathway. In yet another group of tumors, by examining which genes were up-regulated, the authors found activation of a completely different signaling pathway—the PI3K pathway. Further experiments in medulloblastoma-bearing mice revealed that resistance could be delayed or even prevented by including a PI3K inhibitor along with the Smo antagonist in the initial treatment that tumor-bearing animals received. The PI3K inhibitor alone had no effect.

By looking at resistance mechanisms to Smo antagonists before the drug is used in the clinic, the results of this study will better arm oncologists against the molecular defenses that cancers may commandeer to evade this drug. And by identifying a drug combination that delays or even combats development of resistance when used as a first-line treatment in clinical trials, these results could ultimately improve the lives of patients with medulloblastoma or other cancers that depend on Smo for their survival.

Footnotes

  • * These authors contributed equally to this work.

  • Present address: Cancer Research Technology, Gower Street, London WC1E 6BT, UK.

  • Present address: Sanofi-Aventis, 13 Quai Jules Guesde, 94403 Vitry-sur-Seine, France.

  • § Present address: Sanofi-Aventis, Cambridge, MA 02139, USA.

  • Citation: S. Buonamici, J. Williams, M. Morrissey, A. Wang, R. Guo, A. Vattay, K. Hsiao, J. Yuan, J. Green, B. Ospina, Q. Yu, L. Ostrom, P. Fordjour, D. L. Anderson, J. E. Monahan, J. F. Kelleher, S. Peukert, S. Pan, X. Wu, S.-M. Maira, C. García-Echeverría, K. J. Briggs, D. N. Watkins, Y.-m. Yao, C. Lengauer, M. Warmuth, W. R. Sellers, M. Dorsch, Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci. Transl. Med. 2, 51ra70 (2010).

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