mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling.

Unlabelled: mTOR kinase inhibitors block mTORC1 and mTORC2 and thus do not cause the mTORC2 activation of AKT observed with rapamycin. We now show, however, that these drugs have a biphasic effect on AKT. Inhibition of mTORC2 leads to AKT serine 473 (S473) dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and AKT signaling.

Enhancing immunotoxin cell-killing activity via combination therapy with ABT-737.

Immunotoxins are antibody-toxin fusion proteins directed to kill cancer cells displaying specific target antigens on their surface. Remarkably, immunotoxins directed to CD22 on hairy cell leukemia have produced complete remissions in approximately 60% of patients enrolled in phase I/II trials. For reasons that are not yet clear, 40% of patients responded less well.

ABT-737 overcomes resistance to immunotoxin-mediated apoptosis and enhances the delivery of pseudomonas exotoxin-based proteins to the cell cytosol.

Pseudomonas exotoxin (PE)-based immunotoxins (antibody-toxin fusion proteins) have achieved frequent complete remissions in patients with hairy cell leukemia but far fewer objective responses in other cancers. To address possible mechanisms of resistance, we investigated immunotoxin activity in a model system using the colon cancer cell line, DLD1. Despite causing complete inhibition of protein synthesis, there was no evidence that an immunotoxin targeted to the transferrin receptor caused apoptosis in these cells.