A genomic approach to identify molecular pathways associated with chemotherapy resistance

Riedel, Richard F.; Porrello, Alessandro; Pontzer, Emily; Chenette, Emily J.; Hsu, David S.; Balakumaran, Bala S.; Potti, Anil; Nevins, Joseph R.; Febbo, Phillip G.

doi:10.1158/1535-7163.mct-08-0642

Cited by 63 publications

(42 citation statements)

References 33 publications

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“…NSCLC-resistant cell lines underwent epigenetic treatment, and were then compared with the parental and resistant cell lines through microarray assays. The ontology analysis identified a set of genes involved in several tumor progression pathways, similarly to a recently published genomic approach that identified apoptosis as one of the most represented IGFBP-3-methylation as a chemo-resistance biomarker I Ibanez de Caceres et al pathways associated with CDDP-resistance (Riedel et al, 2008). From the nine genes selected for further validation, three were commonly re-expressed in both resistant cell lines, whereas six other genes were specific for each cell line, indicating that CDDP and 5Aza-dC/TSA treatments affect different groups of genes and/or biological pathways, which could explain the high inter-individual variation in drug response described in lung cancer patients (Herbst et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-small-cell lung cancer

et al. 2009

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Cisplatin-based chemotherapy is the paradigm of non-smallcell lung cancer (NSCLC) treatment; however, it also induces de novo DNA-hypermethylation, a process that may be involved in the development of drug-resistant phenotypes by inactivating genes required for drug-cytotoxicity. By using an expression microarray analysis, we aimed to identify those genes reactivated in a set of two cisplatin (CDDP) resistant and sensitive NSCLC cell lines after epigenetic treatment. Gene expression, promoter methylation and CDDP-chemoresponse were further analyzed in three matched sets of sensitive/resistant cell lines, 23 human cancer cell lines and 36 NSCLC specimens. Results revealed specific silencing by promoter hypermethylation of IGFBP-3 in CDDP resistant cells, whereas IGFBP-3 siRNA interference, induced resistance to CDDP in sensitive cells (Po0.001). In addition, we found a strong correlation between methylation status and CDDP response in tumor specimens (Po0.001). Thus, stage I patients, whose tumors harbor an unmethylated promoter, had a trend towards increased disease-free survival (DFS). We report that a loss of IGFBP-3 expression, mediated by promoter-hypermethylation, results in a reduction of tumor cell sensitivity to cisplatin in NSCLC. Basal methylation status of IGFBP-3 before treatment may be a clinical biomarker and a predictor of the chemotherapy outcome, helping to identify patients who are most likely to benefit from CDDP therapy alone or in combination with epigenetic treatment.

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Section: Discussionmentioning

confidence: 99%

IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-small-cell lung cancer

et al. 2009

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“…The PI3K pathway is frequently activated in breast cancer as a result of growth factor receptor activation, HER2 amplification, gain-of-function mutations in PI3Ka, or loss of PTEN (13)(14)(15)(16)(17)(18). In addition, activation of the PI3K pathway has been shown to confer resistance to targeted agents, conventional chemotherapeutics, including taxanes, and radiation therapy (8,(35)(36)(37)(38). Thus, targeting PI3K in combination with docetaxel may provide greater therapeutic benefit in the treatment of breast cancer.…”

Section: Dosing Schedule Of Gdc-0941 In Combination With Docetaxel Inmentioning

confidence: 99%

GDC-0941, a Novel Class I Selective PI3K Inhibitor, Enhances the Efficacy of Docetaxel in Human Breast Cancer Models by Increasing Cell Death In Vitro and In Vivo

Wallin¹,

Guan²,

Prior³

et al. 2012

Clinical Cancer Research

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Purpose: Docetaxel is a front-line standard-of-care chemotherapeutic drug for the treatment of breast cancer. Phosphoinositide 3-kinases (PI3K) are lipid kinases that regulate breast tumor cell growth, migration, and survival. The current study was intended to determine whether GDC-0941, an orally bioavailable class I selective PI3K inhibitor, enhances the antitumor activity of docetaxel in human breast cancer models in vitro and in vivo.Experimental Design: A panel of 25 breast tumor cell lines representing HER2þ, luminal, and basal subtypes were treated with GDC-0941, docetaxel, or the combination of both drugs and assayed for cellular viability, modulation of PI3K pathway markers, and apoptosis induction. Drug combination effects on cellular viability were also assessed in nontransformed MCF10A human mammary epithelial cells. Human xenografts of breast cancer cell lines and patient-derived tumors were used to assess efficacy of GDC-0941 and docetaxel in vivo.Results: Combination of GDC-0941 and docetaxel decreased the cellular viability of breast tumor cell lines in vitro but to variable degrees of drug synergy. Compared with nontransformed MCF10A cells, the addition of both drugs resulted in stronger synergistic effects in a subset of tumor cell lines that were not predicted by breast cancer subtype. In xenograft models, GDC-0941 enhanced the antitumor activity of docetaxel with maximum combination efficacy observed within 1 hour of administering both drugs. GDC-0941 increased the rate of apoptosis in cells arrested in mitosis upon cotreatment with docetaxel.Conclusion: GDC-0941 augments the efficacy of docetaxel by increasing drug-induced apoptosis in breast cancer models.

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“…Nevertheless, most of patients with advanced lung cancer are destined to develop resistance to Taxol (1,2). Although the molecular basis of resistance to Taxol is not well-documented, mounting evidence supports the role of intrinsically or constitutively activated nuclear factor-κB (NF-κB) in affording protection against programmed cell death.…”

Section: Introductionmentioning

confidence: 99%

Nuclear Factor-κB Inhibition by Parthenolide Potentiates the Efficacy of Taxol in Non–Small Cell Lung Cancer In vitro and In vivo

Zhang

Qiu²,

Jin³

et al. 2009

Molecular Cancer Research

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In this study, we have examined the molecular events induced by parthenolide, a sesquiterpene lactone, and explored possible mechanisms of resistance and sensitization of tumor cells to Taxol. We showed that parthenolide could antagonize Taxol-mediated nuclear factor-κB (NF-κB) nuclear translocation and activation and Bcl-xl up-regulation by selectively targeting I-κB kinase activity. In A549 cells, inhibition of nuclear factor-κB by parthenolide resulted in activation of the mitochondrial death pathway to promote cytochrome c release and caspase 3 and 9 activation. In contrast, Taxol alone induced apoptosis via a pathway independent of mitochondria cytochrome c cascade. In addition, depletion of Bcl-xl rescued the apoptotic response to Taxol. Moreover, treatment with parthenolide increased the efficacy of the Taxol-induced inhibition of A549 tumor xenografts in mice. This study elucidated the cellular responses induced by parthenolide that decrease the threshold of mitochodriadependent apoptosis in the treatment of non-small cell lung cancer cells.

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A genomic approach to identify molecular pathways associated with chemotherapy resistance

Cited by 63 publications

References 33 publications

IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-small-cell lung cancer

IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-small-cell lung cancer

GDC-0941, a Novel Class I Selective PI3K Inhibitor, Enhances the Efficacy of Docetaxel in Human Breast Cancer Models by Increasing Cell Death In Vitro and In Vivo

Nuclear Factor-κB Inhibition by Parthenolide Potentiates the Efficacy of Taxol in Non–Small Cell Lung Cancer In vitro and In vivo

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