In vitro and ex vivo gene expression profiling reveals differential kinetic response of HSPs and UPR genes is associated with PI resistance in multiple myeloma.

Abstract

Extensive inter-individual variation in response to chemotherapy (sensitive vs resistant tumors) is a serious cause of concern in the treatment of multiple myeloma (MM). In this study, we used human myeloma cell lines (HMCLs), and patient-derived CD138+ cells to compare kinetic changes in gene expression patterns between innate proteasome inhibitor (PI)-sensitive and PI-resistant HMCLs following test dosing with the second-generation PI Ixazomib. We found 1553 genes that changed significantly post treatment in PI-sensitive HMCLs compared with only seven in PI-resistant HMCLs (p < 0.05). Genes that were uniquely regulated in PI-resistant lines were RICTOR (activated), HNF4A, miR-16-5p (activated), MYCN (inhibited), and MYC (inhibited). Ingenuity pathway analysis (IPA) using top kinetic response genes identified the proteasome ubiquitination pathway (PUP), and nuclear factor erythroid 2-related factor 2 (NRF2)-mediated oxidative stress response as top canonical pathways in Ix-sensitive cell lines and patient-derived cells, whereas EIF2 signaling and mTOR signaling pathways were unique to PI resistance. Further, 10 genes were common between our in vitro and ex vivo post-treatment kinetic PI response profiles and Shaughnessy's GEP80-postBz gene expression signature, including the high-risk PUP gene PSMD4. Notably, we found that heat shock proteins and PUP pathway genes showed significant higher upregulation in Ix-sensitive lines compared with the fold-change in Ix-resistant myelomas.

• Authors: Amit Kumar Mitra, Harish Kumar, Vijay Ramakrishnan, Li Chen, Linda Baughn, Shaji Kumar, S Vincent Rajkumar, Brian G Van Ness
• Journal: Blood cancer journal (Blood Cancer J) Vol. 10 Issue 7 Pg. 78 (07 28 2020) ISSN: 2044-5385 [Electronic] United States
• PMID: 32724061 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Heat-Shock Proteins
• Proteasome Inhibitors

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Biomarkers, Tumor
• Computational Biology
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Heat-Shock Proteins (genetics)
• Humans
• Multiple Myeloma (drug therapy, genetics, pathology)
• Prognosis
• Proteasome Inhibitors (pharmacology, therapeutic use)
• Transcriptome
• Unfolded Protein Response (genetics)