687 Beta-catenin Confers Resistance to PI3K and AKT Inhibitors and Subverts FOXO3a to Promote Metastasis in Colon Cancer

Tenbaum, Stephan P.; Ordóñez‐Morán, Paloma; Puig, Isabel; Chicote, Irene; Arqués, Oriol; Vivancos, Ana; Baselga, J.; Tabernero, Josep; Munoz, Antonia; Pálmer, Héctor G.

doi:10.1016/s0959-8049(12)71330-8

Cited by 47 publications

(61 citation statements)

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“…Zibotentan, a ET(A)R antagonist when combined with the EGFR inhibitor gefitinib, reduces -catenin activity [387]. Furthermore, it has been shown that -cateninmediated resistance to PI3K and AKT inhibitors can be reversed by XAV939 (Table 1), a PARP/Tankyrase blocker [478].…”

Section: Discussionmentioning

confidence: 99%

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Voronkov¹,

Krauß²

2012

CPD

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Wnt/ -catenin signaling is a branch of a functional network that dates back to the first metazoans and it is involved in a broad range of biological systems including stem cells, embryonic development and adult organs. Deregulation of components involved in Wnt/ -catenin signaling has been implicated in a wide spectrum of diseases including a number of cancers and degenerative diseases. The key mediator of Wnt signaling, -catenin, serves several cellular functions. It functions in a dynamic mode at multiple cellular locations, including the plasma membrane, where -catenin contributes to the stabilization of intercellular adhesive complexes, the cytoplasm where -catenin levels are regulated and the nucleus where -catenin is involved in transcriptional regulation and chromatin interactions. Central effectors of -catenin levels are a family of cysteine-rich secreted glycoproteins, known as Wnt morphogens. Through the LRP5/6-Frizzled receptor complex, Wnts regulate the location and activity of the destruction complex and consequently intracellularcatenin levels. However, -catenin levels and their effects on transcriptional programs are also influenced by multiple other factors including hypoxia, inflammation, hepatocyte growth factor-mediated signaling, and the cell adhesion molecule E-cadherin. The broad implications of Wnt/ -catenin signaling in development, in the adult body and in disease render the pathway a prime target for pharmacological research and development. The intricate regulation of -catenin at its various locations provides alternative points for therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Voronkov¹,

Krauß²

2012

CPD

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“…Purified patient-derived cells were genotyped straight after surgical resection of patients' tumors by Sequenom or Haloplex platforms. Genotyping by Sequenom (CLIA panel) was performed as previously described (10). Haloplex Target Enrichment System (Agilent Technologies) was used to capture the complete coding regions of 388 oncogenes and tumor suppressor genes (Supplementary Table S2).…”

Section: Genotypingmentioning

confidence: 99%

“…Cells were fixed in 4% para-formaldehyde (PFA) and immunofluorescent staining was performed as described previously (10).…”

Section: Immunohistochemistry and Immunofluorescencementioning

confidence: 99%

“…Therefore, the efficacy of PI3K and AKT inhibitors can be mediated in part through nuclear relocalization of FOXO proteins and consequent induction of apoptosis. We previously described that Wnt/b-catenin oncogenic signaling confers resistance to FOXO3A-dependent apoptosis promoted by PI3K or AKT-inhibitory drugs (10). Such resistance was driven by nuclear b-catenin that impaired the capacity of FOXO3A to execute its apoptotic program.…”

Section: Introductionmentioning

confidence: 99%

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Tankyrase Inhibition Blocks Wnt/β-Catenin Pathway and Reverts Resistance to PI3K and AKT Inhibitors in the Treatment of Colorectal Cancer

Arqués

Chicote

Puig

et al. 2016

Clinical Cancer Research

150

125

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Purpose: Oncogenic mutations in the KRAS/PI3K/AKT pathway are one of the most frequent alterations in cancer. Although PI3K or AKT inhibitors show promising results in clinical trials, drug resistance frequently emerges. We previously revealed Wnt/b-catenin signaling hyperactivation as responsible for such resistance in colorectal cancer. Here we investigate Wnt-mediated resistance in patients treated with PI3K or AKT inhibitors in clinical trials and evaluate the efficacy of a new Wnt/tankyrase inhibitor, NVP-TNKS656, to overcome such resistance.Experimental Design: Colorectal cancer patient-derived sphere cultures and mouse tumor xenografts were treated with NVP-TNKS656, in combination with PI3K or AKT inhibitors.We analyzed progression-free survival of patients treated with different PI3K/AKT/mTOR inhibitors in correlation with Wnt/b-catenin pathway activation, oncogenic mutations, clinicopathological traits, and gene expression patterns in 40 colorectal cancer baseline tumors.Results: Combination with NVP-TNKS656 promoted apoptosis in PI3K or AKT inhibitor-resistant cells with high nuclear b-catenin content. High FOXO3A activity conferred sensitivity to NVP-TNKS656 treatment. Thirteen of 40 patients presented high nuclear b-catenin content and progressed earlier upon PI3K/AKT/ mTOR inhibition. Nuclear b-catenin levels predicted drug response, whereas clinicopathologic traits, gene expression profiles, or frequent mutations (KRAS, TP53, or PIK3CA) did not.Conclusions: High nuclear b-catenin content independently predicts resistance to PI3K and AKT inhibitors. Combined treatment with a Wnt/tankyrase inhibitor reduces nuclear b-catenin, reverts such resistance, and represses tumor growth. FOXO3A content and activity predicts response to Wnt/b-catenin inhibition and together with b-catenin may be predictive biomarkers of drug response providing a rationale to stratify colorectal cancer patients to be treated with PI3K/AKT/mTOR and Wnt/b-catenin inhibitors.

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“…Furthermore, ectopic Par-4 expression in HT-29 cells was shown to deregulate mRNA's and microRNA's involved in cell migration and motility [16] . Specifically, several target genes of these deregulated miRNA's are part of the Wnt/β-catenin and PI3K/Akt pathways, both of which have been implicated in colon cancer progression and metastasis [22,23] . We have shown in this study that Par-4 can inhibit the ability of colon cancer cell lines, SW480 and SW620, to migrate and invade.…”

Section: Discussionmentioning

confidence: 99%

Overexpression Of Prostate Apoptosis Response Protein-4 In Colon Cancer Cells Can Inhibit Metastasis By Upregulating E-cadherin Expression

Nguyen¹,

Kline²,

Caballero³

et al. 2015

JCRC

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Colon cancer has a five-year survival of 64.7%, and about 50,000 people are expected to die from colon cancer this year. Patients with metastatic colorectal cancer have a significantly worse prognosis, a 12.9% five -year survival. This emphasizes the need for strategies to inhibit the growth and metastases of colorectal cancer. Prostate apoptosis response protein 4 (Par-4) is a pro-apoptotic protein that has been shown to mediate apoptosis in response to stimuli, such as chemotherapeutics and radiation. Recombinant Par-4 protein has been shown to reduce the occurrence of Lewis lung carcinoma metastases in-vivo; however, the mechanism by which Par-4 can inhibit metastasis has not been elucidated. In this study, human colon cancer cell lines -SW480 and SW620 -were transfected with Par-4 plasmid or anti-Par-4 shRNA, and the effect on metastasis was examined. Par-4 overexpression inhibited cell migration and invasion, while Par-4 knockdown promoted it. Moreover, the morphology of SW620 cells was altered when Par-4 levels were increased. The change was characteristic of a mesenchymal-to-epithelial transition (MET) in these cells. MET can be induced by upregulation of E-cadherin expression, and RT-PCR and Western blot analyses showed that E-cadherin mRNA and protein levels, respectively, were increased in the Par-4 overexpressing cells concomitant with a decrease in vimentin. The results of this study demonstrate the potential of Par-4 in colon cancer therapy, not only in primary tumors but also in metastatic cells.

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687 Beta-catenin Confers Resistance to PI3K and AKT Inhibitors and Subverts FOXO3a to Promote Metastasis in Colon Cancer

Cited by 47 publications

References 0 publications

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Tankyrase Inhibition Blocks Wnt/β-Catenin Pathway and Reverts Resistance to PI3K and AKT Inhibitors in the Treatment of Colorectal Cancer

Overexpression Of Prostate Apoptosis Response Protein-4 In Colon Cancer Cells Can Inhibit Metastasis By Upregulating E-cadherin Expression

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