Oncotarget

Research Papers:

Dual PI3K/mTOR inhibition is required to effectively impair microenvironment survival signals in mantle cell lymphoma

Laia Rosich, Arnau Montraveta, Sílvia Xargay-Torrent, Mónica López-Guerra, Jocabed Roldán, Marta Aymerich, Itziar Salaverria, Sílvia Beà, Elías Campo, Patricia Pérez-Galán, Gaël Roué and Dolors Colomer _

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Oncotarget. 2014; 5:6788-6800. https://doi.org/10.18632/oncotarget.2253

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Abstract

Laia Rosich1, Arnau Montraveta1, Sílvia Xargay-Torrent1, Mónica López-Guerra1, Jocabed Roldán1, Marta Aymerich2,3, Itziar Salaverria3, Sílvia Beà3, Elías Campo2,3, Patricia Pérez-Galán1, Gaël Roué1 and Dolors Colomer1,2

1 Experimental Therapeutics in Lymphoid Malignancies Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

2 Hematopathology Unit, Department of Pathology, Hospital Clínic, Barcelona, Spain

3 IDIBAPS, University of Barcelona, Barcelona, Spain

Correspondence:

Dolors Colomer, email:

Keywords: NVP-BEZ235, mantle cell lymphoma, invasion, cytokine signaling

Received: May 12, 2014 Accepted: July 24, 2014 Published: July 25, 2014

Abstract

Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. Antitumor activity has been observed with mTOR inhibitors. However, they have shown limited clinical efficacy in relation to drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we have performed a comparative analysis of the mTOR inhibitor everolimus, the pan-PI3K inhibitor NVP-BKM120 and the dual PI3K/mTOR inhibitor NVP-BEZ235 in primary MCL cells. We found NVP-BEZ235 to be more powerful than everolimus or NVP-BKM120 in PI3K/Akt/mTOR signaling inhibition, indicating that targeting the PI3K/Akt/mTOR pathway at multiple levels is likely to be a more effective strategy for the treatment of MCL than single inhibition of these kinases.  Among the three drugs, NVP-BEZ235 induced the highest change in gene expression profile. Functional validation demonstrated that NVP-BEZ235 inhibited angiogenesis, migration and tumor invasiveness in MCL cells. NVP-BEZ235 was the only drug able to block IL4 and IL6/STAT3 signaling which compromise the therapeutic effect of chemotherapy in MCL. Our findings support the use of the dual PI3K/mTOR inhibitor NVP-BEZ235 as a promising approach to interfere with the microenvironment-related processes in MCL.


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