Pharmacogenomic approach for the identification of novel determinants of acquired resistance to oxaliplatin in colorectal cancer

Martínez-Cardús, Anna; Martínez-Balibrea, Eva; Bandrés, Eva; Malumbres, Raquel; Ginés, Alba; Manzano, José Luís; Tarón, Miquel; García‐Foncillas, Jesús; Abad, Albert

doi:10.1158/1535-7163.mct-08-0659

Cited by 60 publications

(59 citation statements)

References 45 publications

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“…11,[28][29][30] Upregulation of CDK5 was recently identified as one of genetic changes related to oxaliplatin resistance acquisition in colorectal cancer cells. 31 A recent RNAi screening study demonstrated that silencing CDK5 enhanced the sensitivity to a PARP inhibitor in a breast cancer cell line. 32 Our gene expression profile analysis indicated that both CDK5 and CDK5 activators are expressed in myeloma cells.…”

Section: Discussionmentioning

confidence: 99%

RNAi screen of the druggable genome identifies modulators of proteasome inhibitor sensitivity in myeloma including CDK5

Zhu

Tiedemann

Shi

et al. 2011

Blood

101

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The molecular target(s) cooperating with proteasome inhibition in multiple myeloma (MM) remain unknown. We therefore measured proliferation in MM cells transfected with 13 984 small interfering RNAs in the absence or presence of increasing concentrations of bortezomib. We identified 37 genes, which when silenced, are not directly cytotoxic but do synergistically potentiate the growth inhibitory effects of bortezomib. To focus on bortezomib sensitizers, genes that also sensitized MM to melphalan were excluded. When suppressed, the strongest bortezomib sensitizers were the proteasome subunits PSMA5, PSMB2, PSMB3, and PSMB7 providing internal validation, but others included BAZ1B, CDK5, CDC42SE2, MDM4, NME7, RAB8B, TFE3, TNFAIP3, TNK1, TOP1, VAMP2, and YY1. The strongest hit CDK5 also featured prominently in pathway analysis of primary screen data. Cyclin IntroductionBortezomib is a potent and selective proteasome inhibitor used in the treatment of multiple myeloma (MM) and low-grade lymphoma patients. Bortezomib produces significant clinical responses in both newly diagnosed and advanced MM, but only 40% of patients respond to the single agent, 1,2 and the majority of these patients become resistant over time. The mechanism of antimyeloma activity of bortezomib is therefore a subject of intense study with inhibition of the proteasome, autophagy, and activation of the unfolded protein stress response pathway apparently critical. A downstream consequence of proteasome inhibition relevant to MM is blockade of nuclear factor B (NF-B) activity, which may partly mediate bortezomib activity in MM because activating mutations in the NF-B pathway were identified in at least 17% of MM patients and 41% of human myeloma cell lines and appear to mediate accelerated growth and survival of malignant plasma cells. [3][4][5] However, the 35% to 50% response rate to bortezomib cannot be totally interpreted by NF-B abnormality, suggesting that other specific molecular targets, resistance mechanisms, or perhaps unique pharmacokinetics are inherent in patients. Furthermore, resistance to bortezomib therapy often develops even in initially sensitive patients; and although certain mechanisms such as mutations in proteasome subunits have been postulated, 6 the underlying mechanism defining this nonresponsiveness is largely unknown. Understanding the cooperating mechanisms of sensitivity to proteasome inhibition will not only allow more targeted use of proteasome inhibitors but should also make it possible to rationally design synergistic drug combinations and predict patient response to therapy.To begin to address these issues, a druggable genome RNAi screen was used to identify modifiers of bortezomib sensitivity in human MM cells. Through this high-throughput screen, we identified a panel of genes whose loss of expression enhances bortezomib sensitivity (sensitizer). Using shRNA expression systems and a small-molecule inhibitor, we have further validated one of the most potent bortezomib sensitizer genes as cyclin-dependent kinase 5 (...

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Section: Discussionmentioning

confidence: 99%

RNAi screen of the druggable genome identifies modulators of proteasome inhibitor sensitivity in myeloma including CDK5

Zhu

Tiedemann

Shi

et al. 2011

Blood

101

View full text Add to dashboard Cite

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“…Recently, there has been an increase in the understanding of the factors involved in these phenomena. Resistance is a multifactoral process that may include alteration in transport (uptake and efflux), drug detoxification, DNA repair, tolerance to DNA damage, and apoptosis (2)(3)(4). In addition, there are still major gaps in our understanding of the relationships among factors contributing to platinum resistance and their application in the clinic.…”

Section: Introductionmentioning

confidence: 99%

A proteomic approach links decreased pyruvate kinase M2 expression to oxaliplatin resistance in patients with colorectal cancer and in human cell lines

Martínez-Balibrea

Plasencia

Ginés

et al. 2009

Molecular Cancer Therapeutics

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We aimed to gain further understanding of the molecular mechanisms involved in oxaliplatin resistance in colorectal cancer by using a proteomic approach. A 5-fold oxaliplatinresistant cell line, HTOXAR3, was compared with its parental cell line, HT29, using two-dimensional PAGE. Mass spectrometry, Western blot, and real-time quantitative PCR confirmed the down-regulation of pyruvate kinase M2 (PK-M2) in HTOXAR3 cells. In a panel of eight colorectal cancer cell lines, we found a negative correlation between oxaliplatin resistance and PK-M2 mRNA levels (Spearman r = −0.846, P = 0.008). Oxaliplatin exposure in both HT29 and HTOXAR3 led to PK-M2 mRNA up-regulation. PK-M2 mRNA levels were measured by real-time quantitative PCR in 41 tumors treated with oxaliplatin/5-fluorouracil. Tumors with the lowest PK-M2 levels attained the lowest response rates (20% versus 64.5%, P = 0.026). High PK-M2 levels were associated with high p53 levels (P = 0.032). In conclusion, the data provided clearly link PK-M2 expression and oxaliplatin resistance mechanisms and further implicate PK-M2 as a predictive marker of response in patients with oxaliplatintreated colorectal cancer. [Mol Cancer Ther 2009;8(4): 771-8]

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“…GARP has been proposed to serve as a receptor for latent TGF-b, although the relevance of this receptor/ligand interaction is not clear (20,21). Interestingly, numerous studies have reported an amplification of the GARP gene in tumors, in particular in those with an invasive, metastasizing or treatment-resistant potential, suggesting a role of this gene product in regulating aggressive tumor biology once deregulated (22)(23)(24)(25)(26)(27)(28)(29). Clarification of GARP miRNA regulation might therefore have an implication in determining the role of GARP and its regulatory miRNAs in immune responses.…”

mentioning

confidence: 99%

miR-142-3p Is Involved in CD25+ CD4 T Cell Proliferation by Targeting the Expression of Glycoprotein A Repetitions Predominant

Zhou

Haupt

Prots

et al. 2013

The Journal of Immunology

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Because of the numerous targets of microRNAs (miRNAs), functional dissection of specific miRNA/mRNA interactions is important to understand the complex miRNA regulatory mechanisms. Glycoprotein A repetitions predominant (GARP) is specifically expressed on regulatory CD25+ CD4 T cells upon their activation. GARP has a long 3′ untranslated region containing five highly conserved regions suggesting miRNA regulation of its expression. Although GARP is physiologically expressed on a cell subset characterized by stringent control of proliferation, amplification of the GARP gene has been found in many tumors characterized by uncontrolled proliferation. In this study, we investigated in detail miRNA regulation of GARP expression, in particular by miR-142-3p, and dissected the functional outcome of miR-142-3p/GARP mRNA interaction. We demonstrate that miR-142-3p binds directly to the 3′ untranslated region of GARP and represses GARP protein expression by Argonaute 2–associated degradation of GARP mRNA. Functionally, miR-142-3p–mediated regulation of GARP is involved in the expansion of CD25+ CD4 T cells in response to stimulation. The data indicate that miR-142-3p regulates GARP expression on CD25+ CD4 T cells and, as a result, their expansion in response to activation. Our data provide novel insight into the molecular mechanisms controlling regulatory T cell expansion. They may also have implications for understanding tumor cell biology.

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Pharmacogenomic approach for the identification of novel determinants of acquired resistance to oxaliplatin in colorectal cancer

Cited by 60 publications

References 45 publications

RNAi screen of the druggable genome identifies modulators of proteasome inhibitor sensitivity in myeloma including CDK5

RNAi screen of the druggable genome identifies modulators of proteasome inhibitor sensitivity in myeloma including CDK5

A proteomic approach links decreased pyruvate kinase M2 expression to oxaliplatin resistance in patients with colorectal cancer and in human cell lines

miR-142-3p Is Involved in CD25+ CD4 T Cell Proliferation by Targeting the Expression of Glycoprotein A Repetitions Predominant

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