Temsirolimus inhibits cell growth in combination with inhibitors of the B-cell receptor pathway

Abstract

Lately, mTOR inhibitors have gained clinical relevance in malignant lymphoma. Still, rapamycin derivatives may activate a pro-survival feedback loop through PI3K-Akt. In this current study, temsirolimus effectively reduced cell growth in GCB and ABC diffuse large cell B-cell lymphoma (GCB = 30–66%, ABC = 45–57%). Combination treatment with the PI3K-δ inhibitor idelalisib additively effected ABC and GCB lymphoma (GCB = 16–38%, ABC = 25–50%). Since Bruton's Tyrosine Kinase (BTK) plays a significant role for the survival of ABC lymphoma, this study also combined the BTK inhibitor ibrutinib with temsirolimus, which resulted in additive cell growth reduction (ibrutinib 50%, temsirolimus 44%, combination 25%) in ABC lymphoma. In contrast, bortezomib, which has been shown previously to be efficient in ABC lymphoma, revealed an antagonistic effect with temsirolimus in some GCB lymphoma (temsirolimus 53%, temsirolimus + bortezomib 63%). Western blot analysis identified the increase of phosphorylated pro-survival kinases Akt and PDK as a possible underlying mechanism of this interaction.

Keywords::

• DLBCL
• temsirolimus
• mTOR
• PI3K

Acknowledgments

We thank Joseph Buggy and Brian Lannutti for kindly providing ibrutinib and idelalisib, respectively, and Georg Lenz for the ABC DLBCL cell lines. Temsirolimus was provided by Pfizer.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal

Supplementary material available online

Supplementary Figures 1–5 to be found at online http://informahealthcare.com/doi/abs/10.3109/10428194.2015.1023720.