Targeting mTOR for the treatment of B cell malignancies

Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that functions as a key regulator of cell growth, division and survival. Many haematologic malignancies exhibit elevated or aberrant mTOR activation, supporting the launch of numerous clinical trials aimed at evaluating the potential of single agent mTOR-targeted therapies. While promising early clinical data using allosteric mTOR inhibitors (rapamycin and its derivatives, rapalogs) have suggested activity in a subset of haematologic malignancies, these agents have shown limited efficacy in most contexts. Whether the efficacy of these partial mTOR inhibitors might be enhanced by more complete target inhibition is being actively addressed with second generation ATP-competitive mTOR kinase inhibitors (TOR-KIs), which have only recently entered clinical trials. However, emerging preclinical data suggest that despite their biochemical advantage over rapalogs, TOR-KIs may retain a primarily cytostatic response. Rather, combinations of mTOR inhibition with other targeted therapies have demonstrated promising efficacy in several preclinical models. This review investigates the current status of rapalogs and TOR-KIs in B cell malignancies, with an emphasis on emerging preclinical evidence of synergistic combinations involving mTOR inhibition.