2. Academic Validation
  3. TOP2A expression predicts responsiveness to carfilzomib in myeloma and informs novel combinatorial strategies for enhanced proteasome inhibitor cell killing

TOP2A expression predicts responsiveness to carfilzomib in myeloma and informs novel combinatorial strategies for enhanced proteasome inhibitor cell killing

  • Leuk Lymphoma. 2021 Feb;62(2):337-347. doi: 10.1080/10428194.2020.1832659.
Antonia Reale 1,  Tiffany Khong 1,  Sridurga Mithraprabhu 1,  Ioanna Savvidou 1,  Jay Hocking 1 2 3,  Krystal Bergin 1,  Malarmathy Ramachandran 1,  Maoshan Chen 1,  Francesco Dammacco 4,  Roberto Ria 4,  Francesco Silvestris 4,  Angelo Vacca 4,  John Reynolds 5,  Andrew Spencer 1 6 7
Affiliations

Affiliations

  • 1 Myeloma Research Group, Australian Centre for Blood Diseases, The Alfred Hospital/Monash University, Melbourne, Australia.
  • 2 Department of Clinical Haematology, Box Hill, Melbourne, Australia.
  • 3 Myeloma Clinic, The Alfred Centre, Melbourne, Australia.
  • 4 Department of Internal Medicine and Human Oncology, University of Bari 'Aldo Moro', Bari, Italy.
  • 5 Biostatistics Consulting Platform, Faculty of Medicine, Nursing and Health Sciences, Monash University, The Alfred Centre, Melbourne, Australia.
  • 6 Malignant Haematology and Stem Cell Transplantation, The Alfred Hospital, Melbourne, Australia.
  • 7 Department of Clinical Haematology, Monash University, Melbourne, Australia.
PMID: 33131357 DOI: 10.1080/10428194.2020.1832659
Abstract

Microarray was utilized to determine if a genetic signature associated with resistance to carfilzomib (CFZ) could be identified. Twelve human myeloma (MM) cell lines (HMCLs) were treated with CFZ and a cell-viability profile was assessed categorizing HMCLs as sensitive or resistant to CFZ. The gene expression profiles (GEP) of untreated resistant versus sensitive HMCLs revealed 29 differentially expressed genes. TOP2A, an Enzyme involved in cell cycle and proliferation, was overexpressed in carfilzomib-resistant HMCLs. TOP2A protein expression levels, evaluated utilizing trephine biopsy specimens acquired prior to treatment with Proteasome inhibitors, were higher in patients failing to achieve a response when compared to responding patients. Logistic-regression analysis confirmed that TOP2A protein expression was a highly significant predictor of response to PIs (AUC 0.738). Further, the combination of CFZ with TOP2A inhibitors, demonstrated synergistic cytotoxic effects in vitro, providing a rationale for combining Topoisomerase inhibitors with CFZ to overcome resistance in MM.

Keywords

Multiple myeloma; TOP2A; carfilzomib; gene expression profile; proteasome inhibition.

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