Rapamycin shows anticancer activity in primary chronic lymphocytic leukemia cellsin vitro, as single agent and in drug combination

Abstract

The mammalian target of rapamycin inhibitor rapamycin and its analogues show promising anticancer activity in various experimental tumor models and are presently evaluated in clinical trials. We, here, evaluated the in vitro activity of rapamycin with regard to tumor-type specificity and possible mechanisms of drug resistance in 97 tumor cell samples from patients and in a resistance-based cell line panel, using the fluorometric microculture cytotoxicity assay. Rapamycin was dose-dependently cytotoxic in patient tumor cells and in cell lines. In primary cells, rapamycin was more active in hematological than in solid tumor samples, with chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia being the most sensitive tumor types. Considerable inter-individual differences in sensitivity were apparent among CLL samples, but no difference was observed between IGHV mutated and unmutated CLL samples, whereas a tendency to lower rapamycin sensitivity was indicated for samples displaying poor-prognostic genomic markers. Combination experiments in CLL cells indicated that rapamycin acted synergistically with vincristine, cisplatin, chlorambucil and taxotere. These results and the clinically-experienced good tolerance to rapamycin analogues encourage clinical studies of rapamycin in CLL treatment as single agent but also in combination with, e.g., vincristine and chlorambucil.

Targeting the PI3K/AKT/mTOR Pathway in Non-Hodgkin’s Lymphoma: Results, Biology, and Development Strategies

“…Combining rapamycin with chemotherapy, for example, completely bypasses AKT's ability to promote chemotherapy resistance in mouse lymphoma models [11,12]. Studies in cell lines and primary tumor cells in vitro also provide support for rapalog-chemotherapy combinations [43,44]. There are now several trials planned or underway for NHL patients combining chemotherapy agents with the rapalogs, including adding temsirolimus to rituximab (R) and bendamustine for relapsed follicular lymphoma; temsirolimus plus R-cladribine for previously untreated MCL; everolimus plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) for peripheral Tcell lymphoma; and a randomized, placebo-controlled assessment of everolimus as an adjuvant post R-CHOP for DLBCL (Table 2).…”

Perspectives on inhibiting mTOR as a future treatment strategy for hematological malignancies

“…Furthermore, other studies recently reported a pro-apoptotic effect of rapamycin in primary B-CLL cells, thereby emphasizing the therapeutic value of mTOR inhibition in this disease. 90,91 Finally, Zanesi and colleagues showed the ability of rapamycin to improve survival of CLL transgenic mouse. 92 Given these results, clinical trials are ongoing in CLL and results from two phase II clinical trials have been recently published.…”

The PI3K/mTOR inhibitor PF-04691502 induces apoptosis and inhibits microenvironmental signaling in CLL and the Eµ-TCL1 mouse model

“…However, single-isoform inhibitors against PI3Ka/b/d and pan-class-1 PI3K inhibitors in CLL cells have all been reported to induce apoptosis. 22,23 Pharmacologic inhibition of mTOR induces cell cycle arrest and apoptosis in CLL cells [24][25][26] ; however, prolonged inhibition of mTOR is known to disrupt negative feedback loops and cause increased AKT S473 activation in other malignancies. 27,28 Given the important role of both PI3K and mTOR in CLL cell survival, the dual pharmacologic inhibition of both class-1 PI3K and mTOR signaling may offer new therapeutic potential, with the possibility of deeper remissions or as an alternative after resistance to idelalisib.…”