Table 2:
Literature review of “omics” studies on “myeloma” “resistance” published between 2010 and 2016
| CLINICAL STUDIES | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Resistant to | Primary (n) vs CL | Type of Cell Assayed | “Omic” Technology Used | Gene/Protein Expression Database | Pathways Involved in Resistance | Specific Findings | Country | Year | Reference (PMID) | |||||||||||
| Resistance to Proteasome Inhibitors | ||||||||||||||||||||
| 1 | BTZ | (544) | Primary MM cells | GEP | GSE2658 | Cell survival, proliferation, DNA repair | JUN and EGR-1 are critical components in BTZ-induced apoptosis in primary MM cells; knockdown of JUN or EGR-1 resulted in BTZ resistance in MM cell lines | USA | 2010 | (19837979) | ||||||||||
| 2 | BTZ, IMiD, CST | (1) | Drug-resistant extramedullary primary MM | WGS, WES, GEP | NA | 4 somatic insertions/deletions, 38 intrachromosomal rearrangements, 35 translocations, 271 nonsynonymous point mutations in KRAS, PIK3CA, ATM, NF-κB2; Truncating mutation of CRBN, point mutations in proteasome subunit G2 and glucocorticoid receptor | USA | 2013 | (23480694) | |||||||||||
| cGH | NA | Aneuploidy, deletions | del1(p13.2–34.2), monosomy 13, monosomy X | |||||||||||||||||
| 3 | BTZ, DEX | (345) | Primary MM cells | GEP | GSE2658 | Redox homeostasis | SCARA3 upregulation in MM cells results in BTZ and DEX resistance; SCARA3 protects against oxidative stress-induced cell killing | USA | 2013 | (23537707) | ||||||||||
| 4 | BTZ | (417) | Primary NPC (n=22); MGUS (n=44); MM (n=351) | GEP | GSE2658 | BTZ resistance is associated with tupregulation of antioxidant genes (CuZnSOD, GPx-1, GSH); the overexpression of SOD1 induced BTZ resistance while the inhibition of CuZnSOD increased BTZ sensitivity | USA | 2015 | (25485927) | |||||||||||
| 5 | BTZ | NA | Primary MM cells | GEP |
GSE4581 GSE6477 |
Hypoxia-induced and acquired BTZ resistance results in increased TrxR1 expression and NF-κB subunit p65 nuclear protein levels; inhibition of TrxR1 restored sensitivity of MM cells to BTZ and decreased hypoxia induced upregulation of p65 | AUS | 2016 | (26743692) | |||||||||||
| 36 | CFZ | NA | Primary MM cells (MRD) | GEP | GSE70399 | Redox homeostasis, protein handling, apoptosis, inflammation | CFZ resistance is associated with the upregulated expression of Nrf2 target genes which include autophagy related genes GABARAPL1 and SQSTM1/p62. CFZ resistance is also associated with the induction of the unfolded protein response (UPR) and PERK-eIF2α signalling which in turn results in NrF2 overexpression. EIF4E3, a downstream target and positive upstream regulator of NrF2, is upregulated in CFZ-resistant cells. Inhibition of the Nrf2-EIF4E3 axis or the PERK-eIF2α pathway, disruption of redox homeostasis, or the inhibition of fatty acid oxidation conferred sensitivity to CFZ | USA | 2016 | (27626179) | ||||||||||
| CL | CFZ-resistant MM cell line: LP-1/CFZ | GSE78069 | ||||||||||||||||||
| 7 | PAD | (77) | Primary RR MM (to THAL-based regimen) | LC-MS/MS | NA | Reduced response to PAD is associated with: (1) Upregulation of proteasome proteins and molecules related to protein folding; (2) Increased relative abundance of TXN, TXNDC5, thioredoxin-dependent peroxide reductase, and thioredoxin-like protein 1, upregulation of PRDX2/5/6, decreased levels of catalase, myeloperoxidase, and glutathione S-transferase P; (3) Annexin A1/A6 and vimentin downregulation; (4) upregulation of four programmed cell death proteins; (5) downregulation of proteins involved in inflammatory and defence response, apart from MHCII and macrophage migration inhibitory factor which were increased | POL | 2016 | (27527861) | |||||||||||
| 8 | BTZ | NA | Primary MM cells | GEP | NA | BTZ resistance is associated with del(8)(p21) which results in altered expression of genes such as TRAIL-R4, CCDC25, RHOBTB2, PTK2B, SCARA3, MYC, BCL2, and TP53 | SWE | 2015 | (26378933) | |||||||||||
| 9 | BTZ | (20) | BTZ treated primary MM cells | DNA Seq | NA | Protein handling | BTZ resistance results from inactivating XBP1 mutations: XBP1-L167I mutation (mapped to Ire1 splice site on XBP1u); XBP1s-P326R (non-conservative missense mutation within trans-activation domain of Xbp1s) | CAN | 2015 | (24029229) | ||||||||||
| 10 | VMP +/− RD | (7) | Primary MM cells: MRD subclone after Induction therapy | GEP | GSE70399 | BTZ resistance associated with inhibition of pathways involved in protein export, protein processing in ER, N-glycan biosynthesis. Overexpression of cancer related genes: FERMT3, TSPO, ALOX5, NCF4, FLNA, PREX1, PYCARD, MY01G found to contribute to BTZ resistance. Downregulation of cancer related genes: SERPINI1, DUSP11, ALCAM, CCNC, COPZ1, FZD3, E2F5; ER related genes: PDIA5, EMC7; PI related genes: PSMD10, SMILE/TMTC3, PSME3, PSMB6, CAV1 also associated with resistant phenotype | ESP | 2016 | (26755711) | |||||||||||
| 11 | CFZ | CL | MM cell line: NCI-H929/CFZ | GEP | NA | Drug-efflux | Upregulated ABCB1 expression confers resistance to CFZ; ABCB1-hi cells associated with upregulation of ASPM, KIF14, TMPO, ADM, EPAS1, HIF-2α, CXCL12/SDF1, HBEGF | USA | 2013 | (23475625) | ||||||||||
| (6) | Primary MM cells | NA | ||||||||||||||||||
| (304) | Primary MM cells | MMRC reference collection dataset | ||||||||||||||||||
| 12 | BTZ, DOX | (9) | Primary MM cells | GEP | GSE19554 | ALDH1A1 upregulates survival proteins (Akt and BCL2) and contributes to drug resistance; overexpression of ALDH1A1 also led to upregulation of ALDH1A1-RXRα-NEK2 pathway resulting in activation of drug-efflux pump ABCB1 | USA | 2014 | (25230277) | |||||||||||
| 13 | VD or VAD | (24) | Matched diagnostic and relapse primary MM samples | DNA Copy Number + LOH | GSE37459 | Cell cycle | Relapse associated with increase in CNA (diagnosis: 15.8 vs relapse: 19.1); Relapse represented intraclonal evolution and diversification of myeloma; Upregulation of NF-κB genes at relapse; 1q21 gain, TP53 deletions | FRA | 2013 | (22874878) | ||||||||||
| 14 | BTZ | (264) | Primary relapsed MM | GEP | NA | CKS1B expression is increased in relapsed MM and confers drug resistance to BTZ | USA | 2015 | (26156395) | |||||||||||
| 15 | BTZ | (1) | Primary MM cells | DNA Seq | NA | Eight nonsynonymous somatic mutations and several copy number variants including CCND1 and RB1 | JPN | 2015 | (26491355) | |||||||||||
| 16 | BTZ | NA | Primary MM cells (CR vs PD) | GEP | GSE9782 | Plasma cell maturation | Expression of XBP1 target genes lower in PD (BTZ-resistant) tumors; suppression of XBP1s induces BTZ resistance via de-commitment to plasma cell maturation and Ig production resulting in diminished ER front-loading and cytotoxic susceptibility to PI-induced inhibition of ER-associated degradation | CAN | 2015 | (24029229) | ||||||||||
| 17 | VMP +/− RD | (12) | Primary MM cells: MRD subclone after Induction therapy | DNA Copy Number + LOH | GSE70399 | Copy number abnormalities | CNA: 66 CNA (56 losses and 10
gains) uniquely present in either dignostic or MRD clonal PC
population CNN-LOH: 3 patients’ MRD clonal PCs lacked CNN-LOH present at diagnosis, whereas 1 patient’s MRD clonal PCs had a CNN-LOH in chromosome 1 that was not detected at diagnosis |
ESP | 2016 | (26755711) | ||||||||||
| 18 | BTZ | (9) | Primary drug-resistant pre-plasma cells | GEP | NA | Epigenetic | Drug-resistant pre-PCs (CD19- CD138-) are enriched in epigenetic regulators (e.g. histone methyltranferases and demethylases, histone acetyltransferases and deacetylases), suggesting drug resistance is associated with a reversible bidirectional phenotypic transition of myeloma-propagating cells | GBR | 2013 | (23169779) | ||||||||||
| 19 | BTZ | (6) | Primary MM cells (BTZ-responders vs BTZ-resistant) | miRNA array | NA | Resistance to BTZ associated with downregulation of exosomal miR-16–5p, miR-15a-5p, mir-17–5p, and miR-20a-5p | CHN | 2016 | (27129167) | |||||||||||
| Resistance to Conventional Chemotherapy | ||||||||||||||||||||
| 20 | MPH | (357) | CD138+ primary MM cells | GEP | NA | Drug-efflux, protein handling | Resistance associated genes: SLC31A2 (membrane pump), FBXW7, USP6, UBE2J1, Wnt-5a (UPS), CSGAL-NACT1 (component of CD138) | DEN | 2013 | (24376673) | ||||||||||
| 21 | MPH | (12) | Primary MM cells | GEP | GSE2658 | Cell-cycle | Kruppel-like factor 4 (KLF4) expression increased resistance of MM cells to MPH resulting cell cycle blockade; KLF4 associated with induction of p21(Cip1) and p27(Kip1) in cell lines with intact p53 pathway and of p27(Kip1) only in those with impaired p53 pathway | FRA | 2013 | (23585530) | ||||||||||
| 22 | MPH, DEX | CL and Primary | MM cell line: ARP-1 and primary human macrophage cells | GEP | NA | Apoptosis, survival, proliferation | PSGL-1 (P-selectin glycoprotein ligand-1)/selectins and ICAM-1/CD18 contribute to macrophage-mediated myeloma cell drug resistance; interaction of these molecules activated Src and Erk1/2 kinases and c-myc pathways and suppressed caspase activation induced by chemotherapy | USA | 2013 | (22996336) | ||||||||||
| Resistance to Other Therapies | ||||||||||||||||||||
| 23 | Multidrug | (51) | Primary MM cells | GEP | NA | Survival, proliferation | CKS1B overexpression activates downstream STAT3 and MEK/ERK pathways resulting in drug resistance | USA | 2010 | (20930946) | ||||||||||
| 24 | Multidrug | (19) | Primary MM cells | GEP | GSE19554 | NEK2, a chromosome instability gene, is highly associated with drug resistance; overexpression of NEK2 activates Akt and Wnt signalling | USA | 2012 | (23328480) | |||||||||||
| 25 | NK cell lysis | (12) | Primary MM cells | GEP | NA | Antigen presentation | MHCI highly expressed in patient MM cells that were relatively resistant to NK-92 cell lysis | CHN | 2014 | (24850305) | ||||||||||
| PRE-CLINICAL STUDIES | ||||||||||||||||||||
| Resistant to | Type of Cell Assayed | “Omic” Technology Used | Gene/Protein Expression Database | Pathways Involved in Resistance | Specific Findings | Country | Year | Reference (PMID) | ||||||||||||
| Resistance to Proteasome Inhibitors | ||||||||||||||||||||
| 26 | BTZ | MM cell line: KMS-11 | siRNA screen | NA | Plasma cell maturation | Suppression of XBP1s induces BTZ resistance by de-commitment to plasma cell maturation and immunoglobulin production thereby decreasing ER front-loading and cytotoxic susceptibility to PI-induced ERAD | CAN | 2015 | (24029229) | |||||||||||
| IRE1/XBP1 knockdown MM cell line: OCI-MY5 | GEP | GSE44968 | Protein handling | IRE1 knockdown associated with BTZ resistance | ||||||||||||||||
| 27 | BTZ | BTZ-resistant MM cell line: U266/R6 | GEP | NA | HSP88 overexpressed in BTZ-resistant cells; HSPB8 plays important role in elimination of aggregates | FRA | 2014 | (25051369) | ||||||||||||
| 28 | BTZ | BTZ-resistant MM cell lines: KMS-11/BTZ, OPM-2/BTZ | DNA Seq | NA | Ubiquitin-proteasome system | Point mutation (G322A) in PSMB5 gene mediates BTZ resistance | JPN | 2010 | (20555361) | |||||||||||
| 29 | BTZ | Multidrug-resistant MM cell line: RPMI-R5 | GEP | NA | USP24 overexpressed in BTZ-resistant MM cells | ITA | 2011 | (20977926) | ||||||||||||
| 30 | PI | CML cell line: KBM7 | WGS | PRJNA281714 | Resistance to MG132 and bortezomib associated with mutations in 19S proteasome subunit. Cells harbouring PSMC5 or PSMD2 mutations maintained a significant level of 20S proteasome activity in the presence of BTZ treatment | USA | 2015 | PMC4551903 | ||||||||||||
| GEP | PRJNA281613 | Increased resistance to BTZ in cells with 19S subunit reduction associated with suppression of cell cycle (repressed genes involved in DNA replication and cell cycle control), which primes cells to enter a protected, quiescent state | ||||||||||||||||||
| 31 | CFZ | MM cell line: U266 | shRNA screen | NA | 19S proteasomal regulator knockdown induced resistance to CFZ | USA | 2015 | (26327694) | ||||||||||||
| LC-MS/MS | NA | PSMD12 knockdown resulted in selective upregulation of protein turnover pathways such as SQSTM1/p62, UFD1L, and VCP/p97 | ||||||||||||||||||
| 32 | BTZ | MM cell lines: XG1, MDN, SBN, U266, LP1, L363, JJN3, RPMI-8226, NCI-H929 | GEP | NA | Survival, proliferation | Resistance to BTZ associated with induction of REDD1, a negative regulator of mTORC1 activity | FRA | 2010 | (20100206) | |||||||||||
| 33 | BTZ | BTZ-resistant MM cell lines: ANBL-6/BTZ, OPM-2/BTZ, RPMI-8226/BTZ | GEP | NA | IGF-1/IGF-1R signalling contributes to acquired BTZ resistance; OSI-906 (dual IGF-1R and insulin receptor inhibitor) overcame BTZ resistance in cell lines and primary samples in vitro and in vivo | USA | 2012 | (22932796) | ||||||||||||
| 34 | MPH, DOX, BTZ, ETP, STA, tm | MM cell line | GEP | GSE38204 | Drug resistance associated with higher cMET phosphorylation resulting in constitutive activation of cMET-dependent signalling pathways | ITA | 2013 | (23804425) | ||||||||||||
| Drug-resistant MM cell lines: RPMI-8226/R5, MM.1R | Proteome profiler assay | NA | ||||||||||||||||||
| 35 | PI | PI-resistant MM cell lines: LP-1/cIAP2, ANBL-6/cIAP2 | GEP |
GSE4589 GSE5900 |
cIAP2 overexpression confers MM cells with resistance to proteasome inhibitors; 12 target genes of the NF-κB pathway were downregulated; other genes downregulated were IL1RN, TNFAIP2, MBP, IL23A, RelB, FTH1, CTSB, S100A6, ASS1 | SWE | 2015 | (26036313) | ||||||||||||
| 36 | BTZ | BTZ-resistant MM cell line: RPMI-8226/BTZ | GEP | GSE66910 | Autophagy | GRP78-encoding HSPA5 (and hence autophagy) significantly upregulated in BTZ-resistant cells; metformin suppressed GRP78 and enhanced anti-proliferative effect of BTZ | USA | 2014 | (25605012) | |||||||||||
| 37 | BTZ | BTZ-resistant MM cell line: PS-R (U266/BTZ) | GEP | NA | BCL2L11 (Bim) downregulation in BTZ-resistant MM cells resulting in increased cytoprotective autophagy | USA | 2014 | (25208888) | ||||||||||||
| 38 | BTZ | CAF from BTZ-resistant patients | LC-MS/MS | NA | BTZ-resistance parallels activation of oxidative stress and pro-survival autophagy (increase LC3-II and inhibits p62 and p-mTOR) | ITA | 2016 | (26487273) | ||||||||||||
| 39 | CFZ | CFZ-resistant MM cell lines: KMS-11/CFZ, KMS-34/CFZ | GEP | GSE13411 | Cell-cycle | CFZ-resistance associated with autophagy; Kruppel-like factor 4 (KLF4) expression and nuclear localisation were elevated in CFZ-resistant MM cells | USA | 2015 | (26109433) | |||||||||||
| 40 | PI | Multidrug-resistant MM cell line: RPMI-8226/R5 | ITRAQ-MS | NA | Overexpression of myristoylated alanine-rich C-kinase substrate (MARCKS) in drug-resistant R5 cells; pMARCKS promotes cell-cycle progression by facilitating SKP2 expression, suppressing p27(Kip1), and promoting Cyclin E/CDK2 activity to counteract drug-induced cell-cycle arrest | CAN | 2015 | (25179733) | ||||||||||||
| 41 | BTZ | BTZ-resistant Mouse MM cell lines | GEP | GSE41930 | Redox homeostasis | BTZ-sensitive (but not resistant) MM cells upregulate a cluster of NRF-2-mediated oxidative stress response genes: Hspb1, Dnajb1, Hspa1a, Hspa1b, and Ddit3 (CCATT/enhancer-binding protein homologous protein/CHOP); CMAP predicted response to HDACi | USA | 2013 | (23536725) | |||||||||||
| 42 | BTZ, DEX, MPH | MM cell line: MM1.S | GEP | GSE52315 | Hypoxia-induced drug resistance results from upregulation of HIF1A and its target gene LDHA; knockdown of LDHA restores sensitivity to BTZ | USA | 2015 | (25769724) | ||||||||||||
| BTZ | Metabolite Profiling | NA | ||||||||||||||||||
| 43 | BTZ | BTZ-resistant MM cell: ANBL-6/BTZ | Metabolite Profiling | NA | DNA metabolism | Significant alterations in anabolism/catabolism of purines, pyrimidines, and various CoAs between BTZ-resistant and sensitive MM cells | USA | 2014 | (24611431) | |||||||||||
| 44 | BTZ | Mouse MM cell line: 5T33MMvt | GEP | NA | Cytochrome p450 | Dll1/Notch activation contributes to BTZ resistance through downstream upregulation of CYP1A1 | BEL | 2012 | (23111325) | |||||||||||
| Resistance to Immunomodulatory Drugs | ||||||||||||||||||||
| 45 | LEN/POM | OPM2 MM cell line after either CRBN KD or LEN treatment | GEP | GSE31421 | Ubiquitin-proteasome system | Presence of CRBN critical for activity of LEN: NT control, LEN-sensitive cells showed 2-fold expression changes in ~1200 genes while CRBN-depleted, LEN-resistant OPM2 cells showed changes in ~180 genes after LEN treatment | USA | 2011 | (21860026) | |||||||||||
| LEN-resistant MM cell line: MM1.S/LEN | CGH + FISH | GSE31451 | MM1.S: 44 chromosomes, CRBN:
1 copy, MM1.S/LEN: 40-fold reduction of CRBN expression on MM1.S/LEN compared with MM1.S, under-expression of LAPTM4B, ASS1, DDIT4, C6orf190, MAG1, QKI, ANTXR2, COPZ2 |
|||||||||||||||||
| 46 | LEN | Cell Lines: 293FT, U937, MM1S, L363 | (LUC)-ORF Library | NA | LEN binds to cereblon to selectively enhance ubiquitination and proteasomal degradation of IKZF1 and IKZF3 | USA | 2014 | (24292623) | ||||||||||||
| 47 | LEN | MM cell line: MM1.S | SILAC-MS | NA | LEN binds DDB1 and CRBN (forms CRL4 E3 ubiquitin ligase together with CUL4 and ROC1) resulting in increased ubiquitination and proteasomal degradation of IKZF1 and IKZF3 | USA | 2014 | (24292625) | ||||||||||||
| 48 | LEN | LEN-resistant MM cell lines: (R10R) ANBL-6, KAS-6/1, U266, MM1.S | GEP | NA | Survival, proliferation | Activation of Wnt/β-catenin pathway mediates LEN-resistant MM cell lines and primary plasma cell samples while knockdown of β-catenin restores sensitivity to LEN | USA | 2011 | (21189262) | |||||||||||
| 49 | LEN/POM + DEX | In Vivo Murine Model (LEN + DEX or POM+ DEX-resistant MM.1S) | GEP | NA | Resistance to LEN/POM + DEX accompanied by upregulation of MEK/ERK pathway and addition of selumetinib (MEK inhibitor) resensitizes resistant cells | ESP | 2015 | (25102946) | ||||||||||||
| 50 | LEN | LEN-resistant MM cell lines: (R10R) ANBL-6, KAS-6/1, U266, MM1.S | GEP | NA | CAM-DR | Upregulation of CD44 confers CAM-DR in LEN resistant MM cells that could be overcome by Wnt/β-catenin suppression with FH535 and all-trans retinoic acid | USA | 2014 | (23760401) | |||||||||||
| Resistance to Conventional Chemotherapy | ||||||||||||||||||||
| 51 | PRD | PRD-resistant: MM cell line: U266/PRD, RPMI-8226/PRD | GEP | NA | Survival, proliferation, signaling | Upregulation of Rho family of GTPases; downregulation of ETS, NF-κB2; downregulation of TGFβ, SOCS2, SOCS4, WSB2 | TUR | 2012 | (22681910) | |||||||||||
| VICE | VICE-resistant: MM cell line: U266/VICE, RPMI-8226/VICE | Upregulation of TGFβ; Downregulation of Rho family of GTPases; downregulation of SOCS2, SOCS4, WSB2 | ||||||||||||||||||
| 52 | MPH | MPH-resistant MM cell lines: RPMI-8226/LR5, U266/LR6 | LC-MRM | NA | Survival, proliferation, DNA repair, apoptosis | NF-κB signaling, Bcl-2 family of apoptosis-regulating proteins, and Fanconi Anemia DNA repair components contribute to MPH resistance in MM cells | USA | 2011 | (21846842) | |||||||||||
| 53 | ATO | ATO-resistant cell line: RPMI-8226/ATOR05 | GEP | NA | Redox homeostasis | Upregulation of intracellular GSH associated with ATO resistance; cross resistance to MPH and DOX was observed as well | USA | 2012 | (23285138) | |||||||||||
| 54 | MPH | MPH-resistant MM cell line: RPMI-8226/MPH | GEP | GSE60970 | Redox homeostasis, warburg effect | MPH-resistance associated with metabolic switch conforming to Warburg effect (aerobic glycolysis), elevated oxidative stress response mediated by VEGF/IL8-signaling, upregulation of aldo-keto reductase levels of AKR1C family involved in prostaglandin synthesis | NOR | 2015 | (25769101) | |||||||||||
| SILAC-MS | PXD001276 | |||||||||||||||||||
| 55 | DOX | DOX-resistant MM cell line: U266/DOX, RPMI-8226/DOX | miRNA array | NA | Epigenetic | U266/DOX: 9 miRNAs
overexpressed; 16 miRNAs underexpressed RPMI-8226/DOX: 21 miRNAs overexpressed; 26 miRNAs underexpressed |
USA | 2010 | (20357429) | |||||||||||
| MPH | MPH-resistant MM cell line: U266/MPH, RPMI-8226/MPH | U266/MPH: 8 miRNAs
overexpressed; 10 miRNAs underexpressed RPMI-8226/MPH: 12 miRNAs overexpressed; 21 miRNAs underexpressed |
||||||||||||||||||
| 56 | DEX | DEX-resistant MM cell line: MM.1R | miRNA array | NA | 10 and 12 miRNAs upregulated and downregulated respectively in MM.1R cells vs MM.1S. DEX resistance associated with increased miR-221–222 expression and downregulation of PUMA | USA | 2015 | (26249174) | ||||||||||||
| 57 | ADM +
4-OHCY |
MM cell line: RPMI-8226 | GEP | GSE66466 | Chemotherapy increases H3K27me3 that is abrogated by CAM-DR via inactivating phosphorylation of transcription regulator EZH2, resulting in sustained expression of antiapoptotic genes: IGF1, BCL2, HIF1A; inhibition of IGF-1R/PI3K/Akt pathway reversed CAM-DR through EZH2 dephosphorylation and H3K27 hypermethylation | JPN | 2015 | (26517694) | ||||||||||||
| Immunoblot | NA | |||||||||||||||||||
| 58 | DEX | DEX-resistant MM cell line: MM.1R | GEP | GSE59805 | miR-150–5p, miR-26b, miR-125a-5p, miR146–5p, and miR-184 are DEX inducible in MM.1S but not in MM.1R | BEL | 2014 | (25474406) | ||||||||||||
| miRNA array | NA | Cell-cycle | DEX-resistant MM cells did not upregulate genes involved in cell cycle control, cell organisation, cell death, and immunological disease when treated with DEX while DEX-sensitive MM cells upregulated the aforementioned genes | |||||||||||||||||
| 59 | PRD | PRD-resistant: MM cell line: U266/PRD | GEP | NA | Cell-cycle, lipid metabolism | Dowregulation of CDK6, cyclin D3, TNFR, BNIP1, BNIP3, PDCD11, PDCD4, UGCG, ASAH1; overexpression of CDKN2B, CDKN2A, BIRC group of genes, LASS6, SMPD3, DEGS1 | TUR | 2014 | (25330516) | |||||||||||
| VICE | VICE-resistant MM cell line: U266/VICE | Overexpression of cyclin E2, E2F, E2F7, E2F8, TNFAIP6, TNFIP8, BIRC group of genes, BNIP1, BNIP3, PDCD11, PDCD4 | ||||||||||||||||||
| MPH | MPH-resistant MM cell line: U266/MPH | Downregulation of TNFR, CDKN1A, CDKN1C, LASS6, SMPD1 | ||||||||||||||||||
| Resistance to Other Therapies | ||||||||||||||||||||
| 60 | HDACi | Human myeloma cell lines (sensitive, intermediate, resistant) | GEP | NA |
Protein
handling, cytoskeleton |
35-gene signature significantly enriched for 2 pathways in resistant MM cells: (1) regulation of actin cytoskeleton, (2) protein processing in ER | AUS | 2014 | (24651437) | |||||||||||
| 61 | rmhTRAIL | MM cell lines: RPMI-8226 (TRAIL-sensitive); U266 (TRAIL-resistant) | LC-MS/MS | NA | Ubiquitin-proteasome system | Upregulation of small ubiquitin-related modifier 1 and ubiquitin proteasome pathway-related proteins contributes to TRAIL resistance | CHN | 2016 | (27284413) | |||||||||||
| 62 | Geftinib/ Afatinib | MM cell lines: L-363 (NRASmut), LP-1 (NRASwt) | Metabolite Profiling | NA | Pentose phosphate pathway | Significant increased metabolites from Pentose Phosphate Pathway (PPP) associated with Gefitinib resistance | CHN | 2015 | (25894462) | |||||||||||
NA: not available; CL: cell line; HDACi: histone deacetylase inhibitors; CST: corticosteroid; PRD: prednisolone; VICE: vincristine; ATO: arsenic trioxide; ETP: etoposide; STA: staturosporin; tm: tunicamycin; DOX: doxorubicin; MPH: melphalan; DEX: dexamethasone; IMiD: immunomodulatory drugs; THAL: thalidomide; LEN: lenalidomide; POM: pomalidomide, BTZ: bortezomib; CFZ: carfilzomib; VAD: vincristine, adriamycin, dexamethasone; CNA: copy number abnormalities; PI: proteasome inhibitor; CR: complete response; PD: progressive disease; MRD: minimal residual disease; VMP: bortezomib, melphalan, prednisone; RD: lenalidomide, dexamethasone; PAD: bortezomib, doxorubicin, dexamethasone; TXN: thioredoxin; TXNDC5: thioredoxin domain-containing protein 5; rmhTRAIL: recombinant human tumor necrosis factor-related apoptosis-inducing ligand; GSH: Glutathione; GPx-1: Glutathione prooxidant production; TrxR1: Thioredoxin reductase 1; CAF: cancer associated fibroblasts