The Interface between BCR-ABL-Dependent and -Independent Resistance Signaling Pathways in Chronic Myeloid Leukemia

Moraes, Gabriela Nestal de; Souza, Paloma Silva de; Costas, Fernanda; Vasconcelos, Flavia da Cunha; Reis, Flaviana Ruade Souza; Maia, Raquel

doi:10.1155/2012/671702

Cited by 31 publications

(27 citation statements)

References 205 publications

(223 reference statements)

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“…AEG-1/MTDH/LYRIC was recently identified as an oncogene that functions in both drug resistance and metastasis (Nestal de Moraes et al, 2012). Originally discovered as an HIV-1-inducible gene in fetal astrocytes (Kang et al, 2005), AEG-1/MTDH/LYRIC overexpression has now been documented in many cancers, including breast, prostate, esophageal, gastric, renal, colorectal, lung, hepatocellular, ovarian and endometrial cancers, neuroblastoma, glioma and sarcoma (Bhutia et al, 2010; Hu et al, 2009b; Li et al, 2012a; Meng et al, 2011a; Qian et al, 2011; Srivastava et al, 2012a; Srivastava et al, 2012b; Thirkettle et al, 2009b; Wang and Yang, 2011; Ying et al, 2011; Yoo et al, 2010; Yoo et al, 2011a; Yoo et al, 2009b).…”

Section: Introduction: Aeg-1/mtdh/lyric a Gene Involved In Cancermentioning

confidence: 99%

Drug Resistance Mediated by AEG-1/MTDH/LYRIC

Meng

Thiel

Leslie

2013

Advances in Cancer Research

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AEG-1/MTDH/LYRIC has been shown to promote cancer progression and development. Overexpression of AEG-1/MTDH/LYRIC correlates with angiogenesis, metastasis and chemoresistance to various chemotherapy agents in cancer cells originating from a variety of tissues. In this review article, we focus on the role of AEG-1/MTDH/LYRIC in drug resistance. Mechanistic studies have shown that AEG-1/MTDH/LYRIC is involved in classical oncogenic pathways including Ha-Ras, myc, NFκB and PI3K/Akt. AEG-1/MTDH/LYRIC also promotes protective autophagy by activating AMP kinase and autophagy-related gene 5. Another reported mechanism by which AEG-1/MTDH/LYRIC regulates drug resistance is by increasing loading of multidrug resistance gene (MDR) 1 mRNA to the polysome, thereby facilitating MDR1 protein translation. More recently, a novel function for AEG-1/MTDH/LYRIC as an RNA binding protein was elucidated, which has the potential to impact expression of drug sensitivity or resistance genes. Finally, AEG-1/MTDH/LYRIC acts in microRNA-directed gene silencing via an interaction with staphylococcal nuclease and tudor domain containing 1 (SND1), a component of the RNA-induced silencing complex. Altered microRNA expression and activity induced by AEG-1/MTDH/LYRIC represents an additional way that AEG-1/MTDH/LYRIC may cause drug resistance in cancer. The multiple functions of AEG-1/MTDH/LYRIC in drug resistance highlight that it is a viable target as an anti-cancer agent for a wide variety of cancers.

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Section: Introduction: Aeg-1/mtdh/lyric a Gene Involved In Cancermentioning

confidence: 99%

Drug Resistance Mediated by AEG-1/MTDH/LYRIC

Meng

Thiel

Leslie

2013

Advances in Cancer Research

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“…14 We focused our work on further understanding the alternative form of imatinib resistance, BCR-ABL1 independent resistance, which accounts for the other half of all resistance types. 16 For such patients, unknown alternative mutations elsewhere in the genome are hypothesized to be responsible for the nonoptimal response to imatinib treatment. Equally, the accumulation of alternative mutations in CML cells may cause the progression of the pathology from a chronic phase to an accelerated phase and eventually a fatal blast crisis.…”

mentioning

confidence: 99%

A genome‐scale CRISPR knock‐out screen in chronic myeloid leukemia identifies novel drug resistance mechanisms along with intrinsic apoptosis and MAPK signaling

et al. 2020

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Understanding resistance mechanisms in cancer is of utmost importance for the discovery of novel “druggable” targets. Efficient genetic screening, now even more possible with CRISPR‐Cas9 gene‐editing technology, next‐generation sequencing and bioinformatics, is an important tool for deciphering novel cellular processes, such as resistance to treatment in cancer. Imatinib specifically eliminates chronic myeloid leukemia (CML) cells by targeting and blocking the kinase activity of BCR‐ABL1; however, resistance to treatment exists. In order to discover BCR‐ABL1 independent mechanisms of imatinib resistance, we utilized the genome‐scale CRISPR knock‐out library to screen for imatinib‐sensitizing genes in vitro on K562 cells. We revealed genes that seem essential for imatinib‐induced cell death, such as proapoptotic genes (BIM, BAX) or MAPK inhibitor SPRED2. Specifically, reestablishing apoptosis in BIM knock‐out (KO) cells with BH3 mimetics, or inhibiting MAPK signaling in SPRED2 KO cells with MEK inhibitors restores sensitivity to imatinib. In this work, we discovered previously identified pathways and novel pathways that modulate response to imatinib in CML cell lines, such as the implication of the Mediator complex, mRNA processing and protein ubiquitinylation. Targeting these specific genetic lesions with combinational therapy can overcome resistance phenotypes and paves the road for the use of precision oncology.

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“…In general, FOXO3a functions downstream of Bcr–Abl tyrosine kinase in its phosphorylated inactive form in CML, which is reversed by Imatinib activity bringing FOXO3a in its activated form which further increases production of TNF family proteins. Hence TNF superfamily proteins’ production is an indication of imatinib sensitivity [38,39].…”

Section: Resultsmentioning

confidence: 99%

Fast and robust method for drug response biomarker identification and sample stratification

Das¹,

Bhattacharya²

2019

Preprint

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With unprecedented progress of cancer research, the world is now prepared with versatile arsenal of drugs to combat cancer. However, response of an individual to any drug or combination treatment stands as a major challenge and hence there exists the sheer need for personalized medication. Identification of drug response biomarkers from a wholistic tumor microenvironment analysis would guide researchers to develop custom-tailored treatment regimen. In this study, a fast and robust method has been developed to identify drug response biomarkers from entire transcriptomics data analysis in a data-driven manner. The biomarkers which were identified by the method, were able to stratify patients between responders vs non-responders population. Furthermore, bayesian network (BN) analysis, done on the data, brought forth a mechanistic insight into the role of identified biomarkers in regulating drug efficacy. The importance of this work lies with the protocol that is time saving and requires less computation power, yet analyzes a whole system data and helps the researchers to take a step forward towards the development of personalized care in effective cancer treatment.

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The Interface between BCR-ABL-Dependent and -Independent Resistance Signaling Pathways in Chronic Myeloid Leukemia

Cited by 31 publications

References 205 publications

Drug Resistance Mediated by AEG-1/MTDH/LYRIC

Drug Resistance Mediated by AEG-1/MTDH/LYRIC

A genome‐scale CRISPR knock‐out screen in chronic myeloid leukemia identifies novel drug resistance mechanisms along with intrinsic apoptosis and MAPK signaling

Fast and robust method for drug response biomarker identification and sample stratification

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