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

Rosich L, Montraveta A, Xargay-Torrent S, López-Guerra M, Roldán J, Aymerich M, Salaverria I, Beà S, Campo E, Pérez-Galán P, Roué G, Colomer D - Oncotarget (2014)

Bottom Line: Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage.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.NVP-BEZ235 was the only drug able to block IL4 and IL6/STAT3 signaling which compromise the therapeutic effect of chemotherapy in MCL.

View Article: PubMed Central - PubMed

Affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

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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Gene expression profile analysis of primary MCL cells treated with everolimus, NVP-BEZ235 or NVP-BKM120A, Graph depicting the number of differentially expressed genes from each treatment compared to the control of the two MCL cases, with an absolute fold change > 1.5. B, Heatmap illustrating the 619 exclusively expressed genes modulated by NVP-BEZ235 clustered according to unsupervised hierarchical clustering analysis. Samples with similar patterns of expression of the genes studied cluster together, as indicated by the dendogram. Red indicates increased expression and blue decreased expression relative to the median expression level according to the color scale shown. A representative case is shown (MCL nº.2). C, Gene signatures specifically downregulated by NVP-BEZ235 were obtained with GSEA. Bars represent NES (NES < -1.7). FDR < 0.05 was considered significant.
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Figure 2: Gene expression profile analysis of primary MCL cells treated with everolimus, NVP-BEZ235 or NVP-BKM120A, Graph depicting the number of differentially expressed genes from each treatment compared to the control of the two MCL cases, with an absolute fold change > 1.5. B, Heatmap illustrating the 619 exclusively expressed genes modulated by NVP-BEZ235 clustered according to unsupervised hierarchical clustering analysis. Samples with similar patterns of expression of the genes studied cluster together, as indicated by the dendogram. Red indicates increased expression and blue decreased expression relative to the median expression level according to the color scale shown. A representative case is shown (MCL nº.2). C, Gene signatures specifically downregulated by NVP-BEZ235 were obtained with GSEA. Bars represent NES (NES < -1.7). FDR < 0.05 was considered significant.

Mentions: We next analyzed the impact of these PI3K/Akt/mTOR inhibitors on gene expression profile (GEP) of two representative MCL cases (MCL nº.1 and nº.2, Table 1) treated for 8 hours with the corresponding drugs. We selected the common genes between the two MCL cases that were differentially expressed from each treatment compared to the control, with an absolute fold change above 1.5. Everolimus treatment induced the lowest number of gene modulations (118 genes upregulated and 68 downregulated), whereas after NVP-BKM120 treatment 254 genes were upregulated and 290 genes were downregulated. Interestingly, NVP-BEZ235 modulated the highest number of genes, being 319 genes upregulated and 399 downregulated (Figure 2A). Unsupervised hierarchical clustering in each case showed that control and everolimus-treated samples clustered together, consistent with the low number of genes modified by the drug. NVP-BKM120-treated samples clustered with the previous control-everolimus group. Importantly, NVP-BEZ235-treated samples showed the most different gene expression pattern, as indicated by the independent branch of the dendogram (Supplementary Figure A.1). We then selected the genes specifically modulated by NVP-BEZ235 that were not modified by the other inhibitors. Figure 2B shows the heatmap of these 619 genes (281 genes upregulated and 338 genes downregulated) in a representative primary MCL case.


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

Rosich L, Montraveta A, Xargay-Torrent S, López-Guerra M, Roldán J, Aymerich M, Salaverria I, Beà S, Campo E, Pérez-Galán P, Roué G, Colomer D - Oncotarget (2014)

Gene expression profile analysis of primary MCL cells treated with everolimus, NVP-BEZ235 or NVP-BKM120A, Graph depicting the number of differentially expressed genes from each treatment compared to the control of the two MCL cases, with an absolute fold change > 1.5. B, Heatmap illustrating the 619 exclusively expressed genes modulated by NVP-BEZ235 clustered according to unsupervised hierarchical clustering analysis. Samples with similar patterns of expression of the genes studied cluster together, as indicated by the dendogram. Red indicates increased expression and blue decreased expression relative to the median expression level according to the color scale shown. A representative case is shown (MCL nº.2). C, Gene signatures specifically downregulated by NVP-BEZ235 were obtained with GSEA. Bars represent NES (NES < -1.7). FDR < 0.05 was considered significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196163&req=5

Figure 2: Gene expression profile analysis of primary MCL cells treated with everolimus, NVP-BEZ235 or NVP-BKM120A, Graph depicting the number of differentially expressed genes from each treatment compared to the control of the two MCL cases, with an absolute fold change > 1.5. B, Heatmap illustrating the 619 exclusively expressed genes modulated by NVP-BEZ235 clustered according to unsupervised hierarchical clustering analysis. Samples with similar patterns of expression of the genes studied cluster together, as indicated by the dendogram. Red indicates increased expression and blue decreased expression relative to the median expression level according to the color scale shown. A representative case is shown (MCL nº.2). C, Gene signatures specifically downregulated by NVP-BEZ235 were obtained with GSEA. Bars represent NES (NES < -1.7). FDR < 0.05 was considered significant.
Mentions: We next analyzed the impact of these PI3K/Akt/mTOR inhibitors on gene expression profile (GEP) of two representative MCL cases (MCL nº.1 and nº.2, Table 1) treated for 8 hours with the corresponding drugs. We selected the common genes between the two MCL cases that were differentially expressed from each treatment compared to the control, with an absolute fold change above 1.5. Everolimus treatment induced the lowest number of gene modulations (118 genes upregulated and 68 downregulated), whereas after NVP-BKM120 treatment 254 genes were upregulated and 290 genes were downregulated. Interestingly, NVP-BEZ235 modulated the highest number of genes, being 319 genes upregulated and 399 downregulated (Figure 2A). Unsupervised hierarchical clustering in each case showed that control and everolimus-treated samples clustered together, consistent with the low number of genes modified by the drug. NVP-BKM120-treated samples clustered with the previous control-everolimus group. Importantly, NVP-BEZ235-treated samples showed the most different gene expression pattern, as indicated by the independent branch of the dendogram (Supplementary Figure A.1). We then selected the genes specifically modulated by NVP-BEZ235 that were not modified by the other inhibitors. Figure 2B shows the heatmap of these 619 genes (281 genes upregulated and 338 genes downregulated) in a representative primary MCL case.

Bottom Line: Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage.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.NVP-BEZ235 was the only drug able to block IL4 and IL6/STAT3 signaling which compromise the therapeutic effect of chemotherapy in MCL.

View Article: PubMed Central - PubMed

Affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

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.

Show MeSH
Related in: MedlinePlus