Comparative proteomic profiling of refractory/relapsed multiple myeloma reveals biomarkers involved in resistance to bortezomib-based therapy

Abstract

Identifying biomarkers of the resistance in multiple myeloma (MM) is a key research challenge. We aimed to identify proteins that differentiate plasma cells in patients with refractory/relapsed MM (RRMM) who achieved at least very good partial response (VGPR) and in those with reduced response to PAD chemotherapy (bortezomib, doxorubicin and dexamethasone). Comparative proteomic analysis was conducted on pretreatment plasma cells from 77 proteasome inhibitor naïve patients treated subsequently with PAD due to RRMM. To increase data confidence we used two independent proteomic platforms: isobaric Tags for Relative and Absolute Quantitation (iTRAQ) and label free (LF). Proteins were considered as differentially expressed when their accumulation between groups differed by at least 50% in iTRAQ and LF. The proteomic signature revealed 118 proteins (35 up-regulated and 83 down-regulated in ≥ VGPR group). Proteins were classified into four classes: (1) involved in proteasome function; (2) involved in the response to oxidative stress; (3) related to defense response; and (4) regulating the apoptotic process. We confirmed the differential expression of proteasome activator complex subunit 1 (PSME1) by enzyme-linked immunosorbent assay. Increased expression of proteasomes and proteins involved in protection from oxidative stress (eg., TXN, TXNDC5) plays a major role in bortezomib resistance.

Comparative proteomic profiling of sera from patients with refractory multiple myeloma reveals potential biomarkers predicting response to bortezomib-based therapy

“…24 Notably, thioredoxin was found in our previous studies 8,16 to have a potential role in resistance to bortezomib-based chemotherapy. The extracellular location of QSOX1 suggests that it may be involved in remodeling of the extracellular matrix, particularly because QSOX1 can catalyze the formation of disulfide bridges, which are needed for the appropriate folding and stability of various matrix proteins.…”

“…We have recently shown the usefulness of the proteomic approach using bone marrow plasma cells. 8,16 However, due to the cost and inconvenience for patients, bone marrow is not an ideal source of biomarkers in daily practice. To our knowledge, our study is the first analysis of pretreatment sera by modern proteomics in order to establish biomarkers that predict optimal…”

“…These pathways were found in our previous studies performed on pretreatment plasma cells. 8,16 One of the most interesting proteins involved in this pathway is QSOX1, which was found to be upregulated in the PD/SD group. There was a linear trend in the abundance of QSOX1 in all analyzed groups (FIGURE 3).…”

“…Our group has recently proved that proteomics can be successfully used to describe proteins that differentiate the bone marrow plasma cells of patients who have a deep response (ie, CR or VGPR) to bortezomib-based therapy from those of patients who are refractory to the treatment. 8 This led to the description of pathways potentially responsible for resistance. However, obtaining plasma cells from bone marrow biopsy makes this approach too inefficient to identify biomarkers that can be used in clinical practice.…”

Proteomic analysis of serum for identification of potential biomarkers predicting response of patients with refractory multiple myeloma to bortezomib‑based therapy

“…[6][7][8] Bone marrow plasma cells are obtained by an invasive method of bone marrow biopsy, which is not useful in routine clinical practice. Therefore, Łuczak et al 4 have used proteomic analysis of se rum to overcome this obstacle.…”