Predicted mechanisms of resistance to mTOR inhibitors

Abstract

The serine/threonine kinase, mTOR (mammalian Target of Rapamycin) has become a focus for cancer drug development. Rapamycins are highly specific inhibitors of mTOR and potently suppress tumour cell growth by retarding cells in G1 phase or potentially inducing apoptosis. Currently, both rapamycin and several analogues are being evaluated as anticancer agents in clinical trials. Results indicate that many human cancers have intrinsic resistance and tumours initially sensitive to rapamycins become refractory, demonstrating acquired resistance. Here, we consider mechanisms of resistance to inhibitors of mTOR.

Figure 1

Chemical structure of rapamycin and its analogues currently in clinical trials as anticancer chemotherapeutic agents. Bars indicate the chemical modifications to rapamycin.

Figure 2

(A) Predicted mechanisms of resistance to rapamycin analogues. Rapamaycin or its derivatives (red balls) can be eliminated from cells by ABC transporters such as P-glycoprotein. Mutations of FKBP or mTOR (yellow stars) confer resistance. Acquired resistance to rapamycin has been associated with decreased stoichiometry between 4E-BP and eIF4E, either through decreased translation of 4E-BP or overexpression of eIF4E. (B) Inhibition of mTOR leads to decreased translation of cyclin D1 mRNA, and reduced levels of cyclin D1. In many cells, there is a concomitant stabilisation of the cyclin-dependent kinase inhibitor p27^Kip1, and inhibition of CDK-cyclin activity, and decreased phosphorylation of RB. Cells deficient in p27^Kip1 are partially resistant, whereas RB-null cells are completely resistant to inhibition of proliferation by rapamycin.