A gene expression signature distinguishes innate response and resistance to proteasome inhibitors in multiple myeloma

Blood Cancer Journal
A K MitraBrian G Van Ness

Abstract

Extensive interindividual variation in response to chemotherapy is a major stumbling block in achieving desirable efficacy in the treatment of cancers, including multiple myeloma (MM). In this study, our goal was to develop a gene expression signature that predicts response specific to proteasome inhibitor (PI) treatment in MM. Using a well-characterized panel of human myeloma cell lines (HMCLs) representing the biological and genetic heterogeneity of MM, we created an in vitro chemosensitivity profile in response to treatment with the four PIs bortezomib, carfilzomib, ixazomib and oprozomib as single agents. Gene expression profiling was performed using next-generation high-throughput RNA-sequencing. Applying machine learning-based computational approaches including the supervised ensemble learning methods Random forest and Random survival forest, we identified a 42-gene expression signature that could not only distinguish good and poor PI response in the HMCL panel, but could also be successfully applied to four different clinical data sets on MM patients undergoing PI-based chemotherapy to distinguish between extraordinary (good and poor) outcomes. Our results demonstrate the use of in vitro modeling and machine learning-bas...Continue Reading

References

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Citations

Dec 16, 2017·Blood Cancer Journal·Monica K AkreBrian Van Ness
Dec 3, 2017·Cancer Metastasis Reviews·Sara GandolfiPaul G Richardson
Nov 14, 2018·Expert Opinion on Pharmacotherapy·Paul G RichardsonSagar Lonial
May 21, 2019·Expert Opinion on Drug Metabolism & Toxicology·Muhamed Baljevic, Robert Z Orlowski
May 20, 2020·British Journal of Haematology·Ciara L Freeman, Joseph Mikhael
Jun 13, 2018·International Journal of Molecular Sciences·Cinnie Yentia SoekojoWee Joo Chng
Dec 24, 2018·BMC Systems Biology·Saurav Mallik, Zhongming Zhao
May 17, 2018·Journal of Cancer Research and Clinical Oncology·Neale T HankeAmanda F Baker
Dec 1, 2019·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Silpa NarayananZhe-Sheng Chen

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Methods Mentioned

BETA
RNA-seq
ubiquitination

Clinical Trials Mentioned

ISRCTN64455289
NCT01415882

Software Mentioned

Ingenuity Pathway Analysis ( IPA )
Partek Genomics Suite
randomForestSRC
GraphPad Prism
R
QUOTE
IPA
Keatslab
Galaxy

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