Therapeutics:
Means to an end

from Nature Reviews Cancer

Krsitine Novak

Many chemotherapeutic drugs induce cancer-cell apoptosis, so disruption of this pathway is a primary method by which tumours become drug resistant. For example, a survival signalling pathway mediated by the kinase AKT is activated in many tumour types. Scott Lowe and colleagues show that disruption of Akt signalling with the drug rapamycin reverses tumour chemoresistance in a mouse model of lymphoma, so this drug might be used to increase the efficacy of cytotoxic cancer therapies.

Several signalling pathways regulate the fine balance between whether a cell undergoes apoptosis or survival. Much attention has recently been focused on the phosphatidylinositol 3-kinase (PI3K) pathway, which signals through the kinases AKT and TOR. TOR is inhibited by the drug rapamycin, which is used in the clinic as an immunosuppressant. Lowe and colleagues explored the consequences of using rapamycin to inhibit the Akt signalling pathway in their mouse lymphoma model.

Activation of Akt accelerates tumorigenesis and allows tumours to become refractory to chemotherapeutic agents such as cyclophosphamide or doxorubicin. But when Akt signalling was blocked with rapamycin, however, tumours became sensitive to the chemotherapeutic agents. Cancer cells rapidly underwent apoptosis and mice achieved complete remission. The authors showed that rapamycin acted specifically on the Akt signalling pathway — it had no effect on tumours that developed chemoresistance through upregulation of other anti-apoptotic proteins, such as Bcl2. Rapamycin was also not effective as a single agent.

How does AKT–TOR signalling promote cell survival? The kinase TOR normally regulates translation in response to nutrients and growth factors by phosphorylating key components of the protein-synthesis machinery, such as the ribosomal protein S6 kinase p70S6K and the 4E-BP proteins. Phosphorylated 4E-BP then releases the translation initiation factor eIF4E, leading to protein synthesis. So what happens when eIf4e is constitutively activated in this cancer model? Expression of eIf4e accelerated lymphomagenesis in a manner that was similar to Akt, and these tumours also became resistant to chemotherapy. They were not, however, sensitive to rapamycin — presumably because eIf4e acts downstream of Tor.

Clinical trials of rapamycin and its analogues, in combination with other chemotherapeutic agents, are underway. This study reminds us, however, that the tumour genotype should be analysed before patients are given this chemosensitzer — rapamycin would not have an effect on tumours that evade apoptosis through upregulation of BCL2, eIF4E or other pro-survival proteins.

References

	ORIGINAL RESEARCH PAPER Wendel, H. -G. et al. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428, 332–337 (2004)
	FURTHER READING McCormick, F. Cancer: Survival pathways meet their end. Nature 428, 267–269 (2004)