Inhibition of β-Catenin Enhances the Anticancer Effect of Irreversible EGFR-TKI in EGFR-Mutated Non–small-cell Lung Cancer with a T790M Mutation

Togashi, Yosuke; Hayashi, Hidetoshi; Terashima, Masato; Velasco, Marco A. De; Sakai, Kazuko; Fujita, Yoshihiko; Tomida, Shuta; Nakagawa, Kazuhiko; Nishio, Kazuto

doi:10.1097/jto.0000000000000353

Cited by 46 publications

(34 citation statements)

References 48 publications

(58 reference statements)

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“…Apart from the oncogenic role of Wnt signaling in cancer metastasis and invasion, dysregulations of Wnt signaling pathways, particularly the canonical Wnt pathway, have been demonstrated to contribute to therapeutic resistances in many cancer types [31, 37, 44, 69–72]. In this regard, Wnt5a was also found to modulate cell cycle progression and contributes to the chemoresistance in pancreatic cancer cells [70] and regulates ABCB1 expression in multidrug-resistant breast cancer cells through activation of the noncanonical PKA/beta-catenin pathway [48].…”

Section: Discussionmentioning

confidence: 99%

Wnt5a Increases Properties of Lung Cancer Stem Cells and Resistance to Cisplatin through Activation of Wnt5a/PKC Signaling Pathway

Yang

Zhang

et al. 2016

Stem Cells International

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The development of chemoresistance to cisplatin regimens causes a poor prognosis in patients with advanced NSCLC. The role of noncanonical Wnt signaling in the regulation of properties of lung cancer stem cells and chemoresistance was interrogated, by accessing capacities of cell proliferation, migration, invasion, and clonogenicity as well as the apoptosis in A549 cell lines and cisplatin-resistant A549 cells treated with Wnt5a conditional medium or protein kinase C (PKC) inhibitor GF109203X. Results showed that the noncanonical Wnt signaling ligand, Wnt5a, could promote the proliferation, migration, invasion, and colony formation in A549 lung adenocarcinoma cells and cisplatin-resistant A549/DDP cells and increase the fraction of ALDH-positive cell in A549/DDP cells. An exposure of cells to Wnt5a led to a significant reduction of A549/DDP cell apoptosis but not A549 cells. An addition of GF109203X could both strikingly increase the baseline apoptosis and resensitize the Wnt5a-inhibited cell apoptosis. Interestingly, an inhibition of Wnt/PKC signaling pathway could reduce properties of lung cancer stem cells, promote cell apoptosis, and resensitize cisplatin-resistant cells to cisplatin via a caspase/AIF-dependent pathway. These data thus suggested that the Wnt5a could promote lung cancer cell mobility and cisplatin-resistance through a Wnt/PKC signaling pathway and a blockage of this signaling may be an alternative therapeutic strategy for NSCLC patients with resistance to chemotherapies.

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Section: Discussionmentioning

confidence: 99%

Wnt5a Increases Properties of Lung Cancer Stem Cells and Resistance to Cisplatin through Activation of Wnt5a/PKC Signaling Pathway

Yang

Zhang

et al. 2016

Stem Cells International

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“…The growth-inhibitory effects of drugs were examined using a 3,4,-5-dimethyl-2H-tetrazolium bromide assay (MTT; Sigma-Aldrich) (16). The experiment was performed in triplicate.…”

Section: Methodsmentioning

confidence: 99%

“…A western blot analysis was performed as described previously (16). Briefly, subconfluent cells were washed with cold phosphate-buffered saline (PBS) and harvested with lysis A buffer containing 1% Triton X-100, 20 mM Tris-HCl (pH 7.0), 5 mM EDTA, 50 mM sodium chloride, 10 mM sodium pyrophosphate, 50 mM sodium fluoride, 1 mM sodium orthovanadate, and a protease inhibitor mix, Complete™ (Roche Diagnostics).…”

Section: Methodsmentioning

confidence: 99%

MEK inhibitors against MET-amplified non-small cell lung cancer

Chiba¹,

Togashi²,

Tomida³

et al. 2016

International Journal of Oncology

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Several receptor tyrosine kinases (RTKs) including EGFR, ALK, and MET have been identified as therapeutic targets in non-small cell lung cancer (NSCLC). Among the downstream pathways of RTKs, the MAPK pathway is particularly important for cancer cell proliferation, differentiation, and survival. In this study, the effects of MEK inhibitors (trametinib and PD0325901) in several NSCLC cell lines with driver gene alterations, especially RTK genes, were tested in vitro using an MTT assay, and a wide range of sensitivities was found. In particular, all the EGFR-mutated cell lines were resistant to MEK inhibitors, whereas all the MET-amplified cell lines were sensitive. A bioinformatics technique and western blot analyses showed that the PI3K/AKT pathway is more activated in EGFR-mutated NSCLC than in MET-amplified NSCLC, and a PI3K inhibitor enhanced the sensitivity to trametinib in the EGFR-mutated cell lines, suggesting that this pathway is associated with resistance to MEK inhibitors. Although the HCC827 cell line (EGFR mutation) was resistant to MEK inhibitors, the HCC827CNXR cell line, whose driver gene shifts from EGFR to MET, exhibited enhanced sensitivity to MEK inhibitors, indicating the biological importance of the MAPK pathway for MET-amplified NCSLC. Furthermore, a synergistic effect of crizotinib (a MET inhibitor) and trametinib was observed in MET-amplified NCLC cell lines. Our findings indicate that the MAPK pathway is biologically important for MET-amplified NSCLC and strongly encourage the development of combination therapy with a MET inhibitor and a MEK inhibitor against MET-amplified NSCLC.

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“…A large-scale phase III trial (PETACC-8 trial) demonstrated that the BRAF V600E mutation led to shorter disease-free survival and overall survival times in patients with microsatellite-stable colon cancers treated with a combination of leucovorin, fluorouracil and oxaliplatin, with or without cetuximab (29). By contrast, activation of the Wnt/β-catenin pathway led to increased stemness of cancer cells and drug resistance (30)(31)(32)(33). Wnt/β-catenin signaling was constitutively activated in breast cancer stem cells, and blockade of the Wnt/β-catenin pathway inhibited cancer metastasis (30).…”

Section: Discussionmentioning

confidence: 99%

“…Increased nuclear translocation and activation of β-catenin converted CRC cells into cancer stem cells (32). In a non-small-cell lung cancer cell line carrying the EGFR T790M mutation, inhibition of β-catenin activity resulted in inhibition of cancer cell stemness and sensitivity to an irreversible tyrosine kinase inhibitor (33). Taken together, these results indicate that activating BRAF and β-catenin mutations are individual promoters of tumorigenesis and cancer drug resistance, and that the BRAF V600E and CTNNB1 T41A double mutation expands the range of therapeutics that the cancer is resistant to, as well as the complexity and difficulty of developing effective treatments.…”

Section: Discussionmentioning

confidence: 99%

Colon cancers carrying BRAF V600E and β-catenin T41A activating mutations are resistant to numerous common anticancer drugs

Zhang

et al. 2018

Oncol Lett

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Abstract. Colorectal cancer is a common malignancy with a high prevalence and associated mortality rate. However, the preclinical tools currently used for drug development are insufficient. The aim of the present study was to establish and characterize a specific patient-derived colon cancer xenograft (PDCCX) mouse model for drug testing. Primary colon tumors were obtained from 10 patients by surgical resection, and tumor tissues were subsequently grafted into nude mice followed by consecutive passages. Primary tumors and xenograft tumors were collected and processed for DNA sequencing, histological evaluation and immunohistochemical staining. The responses of fifth-generation PDCCX mice to 5-fluorouracil, oxaliplatin, and cetuximab were assessed. Two PDCCX cell lines were successfully established. The histology and protein expression levels of SMAD family member 3, epidermal growth factor receptor, c-MET, caudal type homeobox 2, E-cadherin and β-catenin in the xenograft tumors were consistently maintained from the primary cancer tissues. BRAF V600E and β-catenin T41A double mutations were identified in one cell line, and were associated with a lack of response to 5-fluorouracil, oxaliplatin and cetuximab treatment. This PDCCX cell line may provide a reliable tool for preclinical evaluation of the efficacy of novel therapies that may target the BRAF V600E and β-catenin mutations.

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Inhibition of β-Catenin Enhances the Anticancer Effect of Irreversible EGFR-TKI in EGFR-Mutated Non–small-cell Lung Cancer with a T790M Mutation

Abstract: Our findings indicate that β-Catenin might be a novel therapeutic target in EGFR-mutated NSCLC carrying the T790M mutation.

Cited by 46 publications

References 48 publications

Wnt5a Increases Properties of Lung Cancer Stem Cells and Resistance to Cisplatin through Activation of Wnt5a/PKC Signaling Pathway

Wnt5a Increases Properties of Lung Cancer Stem Cells and Resistance to Cisplatin through Activation of Wnt5a/PKC Signaling Pathway

MEK inhibitors against MET-amplified non-small cell lung cancer

Colon cancers carrying BRAF V600E and β-catenin T41A activating mutations are resistant to numerous common anticancer drugs

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