Expression profiling stratifies mesothelioma tumors and signifies deregulation of spindle checkpoint pathway and microtubule network with therapeutic implications

Malignant pleural mesothelioma (MPM) is a lethal neoplasm exhibiting resistance to most treatment regimens and requires effective therapeutic options. Though an effective strategy in many cancer, targeted therapy is relatively unexplored in MPM because the therapeutically important oncogenic pathway...

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Bibliographic Details
Published in:	Annals of oncology Vol. 25; no. 6; pp. 1184 - 1192
Main Authors:	Suraokar, M.B., Nunez, M.I., Diao, L., Chow, C.W., Kim, D., Behrens, C., Lin, H., Lee, S., Raso, G., Moran, C., Rice, D., Mehran, R., Lee, J.J., Pass, H.I., Wang, J., Momin, A.A., James, B.P., Corvalan, A., Coombes, K., Tsao, A., Wistuba, I.I.
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 01-06-2014 Oxford University Press
Series:	Editor's choice
Subjects:	Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Antineoplastic agents Antineoplastic Agents - pharmacology Biological and medical sciences Blotting, Western Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cell Line, Tumor Cluster Analysis DNA Mutational Analysis epothilone B Epothilones - pharmacology Gene Expression Profiling Humans Immunohistochemistry Lung Neoplasms - genetics M Phase Cell Cycle Checkpoints - genetics MAD2L1 Medical sciences mesothelioma Mesothelioma - genetics Mesothelioma, Malignant microarray Microtubules - pathology Multiple tumors. Solid tumors. Tumors in childhood (general aspects) network Nuclear Proteins - genetics Nuclear Proteins - metabolism Oligonucleotide Array Sequence Analysis Original Pharmacology. Drug treatments Pleural Neoplasms - genetics Pleural Neoplasms - pathology Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction therapeutics Tissue Array Analysis Transcriptome Tubulin Modulators - pharmacology Tumors microarray therapeutics mesothelioma network MAD2L1 epothilone B Antineoplastic agent Mesothelioma Malignant tumor Gene expression profile Epothilone derivatives Treatment Network Cytoskeleton Patupilone Microtubule Control point Cancer
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Summary:	Malignant pleural mesothelioma (MPM) is a lethal neoplasm exhibiting resistance to most treatment regimens and requires effective therapeutic options. Though an effective strategy in many cancer, targeted therapy is relatively unexplored in MPM because the therapeutically important oncogenic pathways and networks in MPM are largely unknown. We carried out gene expression microarray profiling of 53 surgically resected MPMs tumors along with paired normal tissue. We also carried out whole transcriptomic sequence (RNA-seq) analysis on eight tumor specimens. Taqman-based quantitative Reverse-transcription polymerase chain reaction (qRT-PCR), western analysis and immunohistochemistry (IHC) analysis of mitotic arrest deficient-like 1 (MAD2L1) was carried out on tissue specimens. Cell viability assays of MPM cell lines were carried out to assess sensitivity to specific small molecule inhibitors. Bioinformatics analysis of the microarray data followed by pathway analysis revealed that the mitotic spindle assembly checkpoint (MSAC) pathway was most significantly altered in MPM tumors with upregulation of 18 component genes, including MAD2L1 gene. We validated the microarray data for MAD2L1 expression using quantitative qRT-PCR and western blot analysis on tissue lysates. Additionally, we analyzed expression of the MAD2L1 protein by IHC using an independent tissue microarray set of 80 MPM tissue samples. Robust clustering of gene expression data revealed three novel subgroups of tumors, with unique expression profiles, and showed differential expression of MSAC pathway genes. Network analysis of the microarray data showed the cytoskeleton/spindle microtubules network was the second-most significantly affected network. We also demonstrate that a nontaxane small molecule inhibitor, epothilone B, targeting the microtubules have great efficacy in decreasing viability of 14 MPM cell lines. Overall, our findings show that MPM tumors have significant deregulation of the MSAC pathway and the microtubule network, it can be classified into three novel molecular subgroups of potential therapeutic importance and epothilone B is a promising therapeutic agent for MPM.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0923-7534 1569-8041
DOI:	10.1093/annonc/mdu127