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Emerging Therapeutic Strategies to Overcome Drug Resistance in Multiple Myeloma.

ABSTRACT: Multiple myeloma is a malignant plasma cell neoplasm that remains incurable and is ultimately fatal when patients acquire multi-drug resistance. Thus, advancing our understanding of the mechanisms behind drug resistance in multi-relapsed patients is critical for developing better strategies to extend their lifespan. Here, we review the understanding of resistance to the three key drug classes approved for multiple myeloma treatment: immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies. We consider how the complex, heterogenous biology of multiple myeloma may influence the acquisition of drug resistance and reflect on the gaps in knowledge where additional research is needed to improve our treatment approaches. Fortunately, many agents are currently being evaluated preclinically and in clinical trials that have the potential to overcome or delay drug resistance, including next-generation immunomodulatory drugs and proteasome inhibitors, novel small molecule drugs, chimeric antigen receptor T cells, antibody-drug conjugates, and bispecific antibodies. For each class, we discuss the potential of these strategies to overcome resistance through modifying agents within each class or new classes without cross-resistance to currently available drugs.

SUBMITTER: Davis LN

PROVIDER: S-EPMC8038312 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Breast cancer is the most frequent type of malignancy in women worldwide, and drug resistance to the available systemic therapies remains a major challenge. At the molecular level, breast cancer is heterogeneous, where the cancer-initiating stem-like cells (bCSCs) comprise a small yet distinct population of cells within the tumor microenvironment (TME) that can differentiate into cells of multiple lineages, displaying varying degrees of cellular differentiation, enhanced metastatic potential, invasiveness, and resistance to radio- and chemotherapy. Based on the expression of estrogen and progesterone hormone receptors, expression of human epidermal growth factor receptor 2 (HER2), and/or BRCA mutations, the breast cancer molecular subtypes are identified as TNBC, HER2 enriched, luminal A, and luminal B. Management of breast cancer primarily involves resection of the tumor, followed by radiotherapy, and systemic therapies including endocrine therapies for hormone-responsive breast cancers; HER2-targeted therapy for HER2-enriched breast cancers; chemotherapy and poly (ADP-ribose) polymerase inhibitors for TNBC, and the recent development of immunotherapy. However, the complex crosstalk between the malignant cells and stromal cells in the breast TME, rewiring of the many different signaling networks, and bCSC-mediated processes, all contribute to overall drug resistance in breast cancer. However, strategically targeting bCSCs to reverse chemoresistance and increase drug sensitivity is an underexplored stream in breast cancer research. The recent identification of dysregulated miRNAs/ncRNAs/mRNAs signatures in bCSCs and their crosstalk with many cellular signaling pathways has uncovered promising molecular leads to be used as potential therapeutic targets in drug-resistant situations. Moreover, therapies that can induce alternate forms of regulated cell death including ferroptosis, pyroptosis, and immunotherapy; drugs targeting bCSC metabolism; and nanoparticle therapy are the upcoming approaches to target the bCSCs overcome drug resistance. Thus, individualizing treatment strategies will eliminate the minimal residual disease, resulting in better pathological and complete response in drug-resistant scenarios. This review summarizes basic understanding of breast cancer subtypes, concept of bCSCs, molecular basis of drug resistance, dysregulated miRNAs/ncRNAs patterns in bCSCs, and future perspective of developing anticancer therapeutics to address breast cancer drug resistance.

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Emerging Therapeutic Strategies to Overcome Drug Resistance in Multiple Myeloma.

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