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

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-based approaches to establish predictive biomarkers of response and resistance to drugs that may serve to better direct myeloma patient treatment options.

Human primary liver cancer organoids reveal intratumor and interpatient drug response heterogeneity

“…However, in terms of predicting response to the pan-effective drugs discovered here, no known genetic alteration (mutational or otherwise) predicts the response of human cancers to proteasome inhibitors (35,36). Furthermore, early transcriptomic biomarkers of sensitivity to proteasome inhibitors had not yet been clinically validated (35)(36)(37). In addition, HDAC inhibitors also appear to be pan-effective, which is mechanistically plausible given that chromatin-modifying genes were found in one of our earlier studies as top mutated genes in CCA (38).…”

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

“…Identifying the full range of PI mechanisms of action remains relevant given that acquired PI resistance is clinically widespread but its origins remain unclear 7,8 . Finding new methods to specifically target PI-resistant disease, or molecules to synergize with PIs to avoid resistance by driving deeper remissions, remains a long-standing goal.…”

Characterization of carfilzomib-resistant non-small cell lung cancer cell lines

“…Therefore, cells that are initially highly sensitive to CFZ because of low Pgp may have the potential to become highly resistant once Pgp upregulation occurs. In addition to Pgp, gene profiling has identified additional adaptive changes in the CFZ-resistant cells compared to parental cells (Mitra et al 2017;Riz et al 2015;Riz et al 2016;Zheng et al 2017).…”