Cancer drug resistance in multiple myeloma

Uckun, Fatih M.

doi:10.20517/cdr.2022.32

Cited by 7 publications

(10 citation statements)

References 43 publications

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“…The combination of PIs with JAK inhibitors may potentiate their pro-apoptotic activity against MM cells. Likewise, JAK inhibitors could be combined with other apoptosis-inducing MM drugs, such as the BCL-2 homology 3 (BH3)-mimetic Venetoclax and inhibitors of MCL-1 such as AMG-176 and MIK665 [ 1 ]. Recently, serious concerns have emerged regarding the safety profile of JAK inhibitors, especially JAK3 inhibitor Tofacitinib as well as Baricitinib, and Upadacitinib [ 98 ].…”

Section: Discussionmentioning

confidence: 99%

“…Multiple myeloma (MM) is the second most common B-lineage lymphoid malignancy [ 1 , 2 ]. Recent therapeutic advances, including the incorporation of immunomodulatory drugs (IMIDs) and proteasome inhibitors (PI) into frontline and salvage regimens, have significantly improved the survival outcome of multiple myeloma (MM) [ 2 ], but treatment failures and relapse are still common due to inherent and/or acquired cancer drug resistance coupled with an immunosuppressive tumor microenvironment facilitating the immune evasion by drug-resistant MM clones [ 2 - 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…MM patients with triple-class-refractory disease whose malignant clones are characterized by resistance to PIs, IMiDs, and monoclonal antibodies have an overall survival of <6 months emphasizing the urgency of identifying effective strategies to overcome triple-class cancer drug resistance [ 3 , 4 ]. Due to the disappointingly poor outcome of MM patients following a relapse on contemporary frontline regimens, effective treatment strategies for relapsed/refractory MM are urgently needed [ 1 , 2 , 4 , 5 , 8 ]. Personalized therapy platforms, such as precision medicines, bispecific antibodies, CAR-T cells, and antibody therapeutics continue to contribute to improved survival outcomes and thereby change the therapeutic landscape for MM [ 2 , 6 - 9 ].…”

Section: Introductionmentioning

confidence: 99%

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ERBB1/EGFR and JAK3 Tyrosine Kinases as Potential Therapeutic Targets in High-Risk Multiple Myeloma

Uckun

Qazi

2022

Onco

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Our main objective was to identify abundantly expressed tyrosine kinases in multiple myeloma (MM) as potential therapeutic targets. We first compared the transcriptomes of malignant plasma cells from newly diagnosed MM patients who were risk-categorized based on the patient-specific EMC-92/SKY-92 gene expression signature values vs. normal plasma cells from healthy volunteers using archived datasets from the HOVON65/GMMG-HD4 randomized Phase 3 study evaluating the clinical efficacy of bortezomib induction/maintenance versus classic cytotoxic drugs and thalidomide maintenance. In particular, ERBB1/EGFR was significantly overexpressed in MM cells in comparison to normal control plasma cells, and it was differentially overexpressed in MM cells from high-risk patients. Amplified expression of EGFR/ERBB1 mRNA in MM cells was positively correlated with increased expression levels of mRNAs for several DNA binding proteins and transcription factors with known upregulating activity on EGFR/ERBB1 gene expression. MM patients with the highest ERBB1/EGFR expression level had significantly shorter PFS and OS times than patients with the lowest ERBB1/EGFR expression level. High expression levels of EGFR/ERBB1 were associated with significantly increased hazard ratios for unfavorable PFS and OS outcomes in both univariate and multivariate Cox proportional hazards models. The impact of high EGFR/ERBB1 expression on the PFS and OS outcomes remained significant even after accounting for the prognostic effects of other covariates. These results regarding the prognostic effect of EGFR/ERBB1 expression were validated using the MMRF-CoMMpass RNAseq dataset generated in patients treated with more recently applied drug combinations included in contemporary induction regimens. Our findings provide new insights regarding the molecular mechanism and potential clinical significance of upregulated EGFR/ERBB1 expression in MM.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ERBB1/EGFR and JAK3 Tyrosine Kinases as Potential Therapeutic Targets in High-Risk Multiple Myeloma

Uckun

Qazi

2022

Onco

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“…117 Some studies have tried to explain the prognostic role of miRNAs in hematological malignancies, including MM. 118–120 We summarize the widely validated and universally relevant miRNAs in multiple myeloma progression in Table 1.…”

Section: Prognosis and The Role Of Mirnasmentioning

confidence: 99%

miRNAs and Multiple Myeloma: Focus on the Pathogenesis, Prognosis, and Drug Resistance

Tavakoli Pirzaman,

Ebrahimi,

Hasanpour

et al. 2023

Technol Cancer Res Treat

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Multiple myeloma (MM) produces clonal plasma cells and aberrant monoclonal antibody accumulation in patients’ bone marrow (BM). Around 1% of all cancers and 13% of hematological malignancies are caused by MM, making it one of the most common types of cancer. Diagnostic and therapeutic methods for managing MM are currently undergoing extensive research. MicroRNAs (miRNAs) are short noncoding RNAs that reduce or inhibit the translation of their target mRNA after transcription. Because miRNAs play an influential role in how myeloma develops, resources, and becomes resistant to drugs, miRNA signatures may be used to diagnose, do prognosis, and treat the myeloma response. Consequently, researchers have investigated the levels of miRNA in plasma cells from MM patients and developed tools to test whether they directly impacted tumor growth. This review discusses the latest discoveries in miRNA science and their role in the development of MM. We also emphasize the potential applications of miRNAs to diagnose, prognosticate, and treat MM in the future.

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“…[16] In spite of satisfying efficacy in cancer treatment, both intrinsic and acquired drug resistance of cancer cells hamper partially the success of microtubule-targeting chemotherapies. [8,[16][17][18] In addition to drug resistance, several other side effects, among them neurotoxicity and myelosuppression, implicate a dose and time limitation in clinical applicability of anti-microtubule agents. [17,19] Therefore, currently great interest is focused on the identification of novel tubulin-targeting molecules characterized by weak side effects and evasiveness to chemoresistance mechanisms, to provide significant clinical benefits to patients.…”

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confidence: 99%

Biological evaluation of [4‐(4‐aminophenyl)‐1‐(4‐fluorophenyl)‐1H‐pyrrol‐3‐yl](3,4,5‐trimethoxyphenyl)methanone as potential antineoplastic agent in 2D and 3D breast cancer models

Mazzoccoli,

Crispo,

Laurenzana

et al. 2023

Archiv der Pharmazie

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Targeting tubulin polymerization and depolymerization represents a promising approach to treat solid tumors. In this study, we investigated the molecular mechanisms underlying the anticancer effects of a structurally novel tubulin inhibitor, [4‐(4‐aminophenyl)‐1‐(4‐fluorophenyl)‐1H‐pyrrol‐3‐yl](3,4,5‐trimethoxyphenyl)methanone (ARDAP), in two‐ and three‐dimensional MCF‐7 breast cancer models. At sub‐cytotoxic concentrations, ARDAP showed a marked decrease in cell proliferation, colony formation, and ATP intracellular content in MCF‐7 cells, by acting through a cytostatic mechanism. Additionally, drug exposure caused blockage of the epithelial‐to‐mesenchymal transition (EMT). In 3D cell culture, ARDAP negatively affected tumor spheroid growth, with inhibition of spheroid formation and reduction of ATP concentration levels. Notably, ARDAP exposure promoted the differentiation of MCF‐7 cells by inducing: (i) expression decrease of Oct4 and Sox2 stemness markers, both in 2D and 3D models, and (ii) downregulation of the stem cell surface marker CD133 in 2D cell cultures. Interestingly, treated MCF7 cells displayed a major sensitivity to cytotoxic effects of the conventional chemotherapeutic drug doxorubicin. In addition, although exhibiting growth inhibitory effects against breast cancer cells, ARDAP showed insignificant harm to MCF10A healthy cells. Collectively, our results highlight the potential of ARDAP to emerge as a new chemotherapeutic agent or adjuvant compound in chemotherapeutic treatments.

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Cancer drug resistance in multiple myeloma

Cited by 7 publications

References 43 publications

ERBB1/EGFR and JAK3 Tyrosine Kinases as Potential Therapeutic Targets in High-Risk Multiple Myeloma

ERBB1/EGFR and JAK3 Tyrosine Kinases as Potential Therapeutic Targets in High-Risk Multiple Myeloma

miRNAs and Multiple Myeloma: Focus on the Pathogenesis, Prognosis, and Drug Resistance

Biological evaluation of [4‐(4‐aminophenyl)‐1‐(4‐fluorophenyl)‐1H‐pyrrol‐3‐yl](3,4,5‐trimethoxyphenyl)methanone as potential antineoplastic agent in 2D and 3D breast cancer models

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