Genetic biomarkers of drug resistance: A compass of prognosis and targeted therapy in acute myeloid leukemia

Long, Laura J.; Assaraf, Yehuda G.; Lei, Zi‐Ning; Peng, Hongwei; Yang, Lin; Chen, Zhe‐Sheng; Ren, Shiquan

doi:10.1016/j.drup.2020.100703

Cited by 32 publications

(23 citation statements)

References 305 publications

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“…Tumor cell heterogeneity, especially cancer stem-like cells (CSCs), is another cause leading to various resistance responses for multiple therapies (Housman et al, 2014;Steinbichler et al, 2018). Accordingly, multiple studies have addressed intracellular response, including genetic or epigenetic alterations, for cell survival under the death pressure induced by therapies (Cheng et al, 2020;Jiang W. et al, 2020;Long et al, 2020;Wang et al, 2020). New viewpoints and theories have proposed that tumor progression, especially when confronted with external pressure from various therapies, is a dynamic and complicated process that tightly interacts with the surrounding environment (Hanahan, 2014).…”

Section: Introductionmentioning

confidence: 99%

Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment

Gao

et al. 2021

Front. Cell Dev. Biol.

105

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Cancer is a disease which frequently has a poor prognosis. Although multiple therapeutic strategies have been developed for various cancers, including chemotherapy, radiotherapy, and immunotherapy, resistance to these treatments frequently impedes the clinical outcomes. Besides the active resistance driven by genetic and epigenetic alterations in tumor cells, the tumor microenvironment (TME) has also been reported to be a crucial regulator in tumorigenesis, progression, and resistance. Here, we propose that the adaptive mechanisms of tumor resistance are closely connected with the TME rather than depending on non-cell-autonomous changes in response to clinical treatment. Although the comprehensive understanding of adaptive mechanisms driven by the TME need further investigation to fully elucidate the mechanisms of tumor therapeutic resistance, many clinical treatments targeting the TME have been successful. In this review, we report on recent advances concerning the molecular events and important factors involved in the TME, particularly focusing on the contributions of the TME to adaptive resistance, and provide insights into potential therapeutic methods or translational medicine targeting the TME to overcome resistance to therapy in clinical treatment.

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Section: Introductionmentioning

confidence: 99%

Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment

Gao

et al. 2021

Front. Cell Dev. Biol.

105

View full text Add to dashboard Cite

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“…The development of additional therapies focused on targeted genomic, molecular or cellular subgroups aims to create drugs that are more effective and less toxic [ 6 ]. Such therapies include inhibitors of molecular aberrations, pro-apoptotic agents, microenvironment-target molecules, cell cycle checkpoint inhibitors, epigenetic regulators, monoclonal and bispecific antibodies, and cells with a chimeric-specific receptor (CAR cells), among others [ 11 , 14 , 15 , 16 , 17 ]. The clinical activity of some of these drugs has been described as “promising”, while others have been approved by the FDA or are in clinical phases I, II or III trials ( Table 2 ).…”

Section: Acute Myeloid Leukemia (Aml) and Its Treatmentmentioning

confidence: 99%

Inhibitors of Chemoresistance Pathways in Combination with Ara-C to Overcome Multidrug Resistance in AML. A Mini Review

Fajardo-Orduña

Ledesma‐Martínez

Aguíñiga-Sánchez

et al. 2021

IJMS

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Acute myeloid leukemia (AML), the most common type of leukemia in older adults, is a heterogeneous disease that originates from the clonal expansion of undifferentiated hematopoietic progenitor cells. These cells present a remarkable variety of genes and proteins with altered expression and function. Despite significant advances in understanding the molecular panorama of AML and the development of therapies that target mutations, survival has not improved significantly, and the therapy standard is still based on highly toxic chemotherapy, which includes cytarabine (Ara-C) and allogeneic hematopoietic cell transplantation. Approximately 60% of AML patients respond favorably to these treatments and go into complete remission; however, most eventually relapse, develop refractory disease or chemoresistance, and do not survive for more than five years. Therefore, drug resistance that initially occurs in leukemic cells (primary resistance) or that develops during or after treatment (acquired resistance) has become the main obstacle to AML treatment. In this work, the main molecules responsible for generating chemoresistance to Ara-C in AML are discussed, as well as some of the newer strategies to overcome it, such as the inclusion of molecules that can induce synergistic cytotoxicity with Ara-C (MNKI-8e, emodin, metformin and niclosamide), subtoxic concentrations of chemotherapy (PD0332991), and potently antineoplastic treatments that do not damage nonmalignant cells (heteronemin or hydroxyurea + azidothymidine).

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“…Multidrug resistance (MDR) efflux transporters of the ABC (ATP-binding cassette) family comprehend the P glycoprotein (P-gp) pump, encoded by the ABCB1 gene, the multidrug resistance-associated protein 1 (MRP1, encoded by ABCC1 ) and the breast cancer resistance protein (BCRP, encoded by ABCG2 ) [ 38 ]. These ABC efflux pumps are able to extrude endogenous uncharged molecules such as cyclic nucleotides or leukotrienes but also cytotoxic drugs including Ara-C, Vinca alkaloids and epipodophyllotoxins, in the attempt to defend HSCs [ 39 , 40 ]. Differently from P-gp pumps, MRP1 is specific for organic anions while BCRPs efflux substances such as mitoxantrone, methotrexate and others [ 41 , 42 ].…”

Section: Mechanisms Of Therapeutic Resistancementioning

confidence: 99%

Deciphering the Therapeutic Resistance in Acute Myeloid Leukemia

Gurnari

Pagliuca

Visconte

2020

IJMS

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Acute myeloid leukemia (AML) is a clonal hematopoietic disorder characterized by abnormal proliferation, lack of cellular differentiation, and infiltration of bone marrow, peripheral blood, or other organs. Induction failure and in general resistance to chemotherapeutic agents represent a hindrance for improving survival outcomes in AML. Here, we review the latest insights in AML biology concerning refractoriness to therapies with a specific focus on cytarabine and daunorubicin which still represent milestones agents for inducing therapeutic response and disease eradication. However, failure to achieve complete remission in AML is still high especially in elderly patients (40–60% in patients >65 years old). Several lines of basic and clinical research have been employed to improve the achievement of complete remission. These lines of research include molecular targeted therapy and more recently immunotherapy. In terms of molecular targeted therapies, specific attention is given to DNMT3A and TP53 mutant AML by reviewing the mechanisms underlying epigenetic therapies’ (e.g., hypomethylating agents) resistance and providing critical points and hints for possible future therapies overcoming AML refractoriness.

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Genetic biomarkers of drug resistance: A compass of prognosis and targeted therapy in acute myeloid leukemia

Cited by 32 publications

References 305 publications

Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment

Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment

Inhibitors of Chemoresistance Pathways in Combination with Ara-C to Overcome Multidrug Resistance in AML. A Mini Review

Deciphering the Therapeutic Resistance in Acute Myeloid Leukemia

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