Activation of insulin-like growth factor receptor signaling mediates resistance to histone deacetylase inhibitors

Lee, Su Chan; Min, Hye Young; Park, Kwan Hee; Hyun, Sangwon; Kwon, So Jung; Choi, Seok Cheol; Kim, Woo Young; Hj, Lee; Lee, Ho‐Young

doi:10.1016/j.canlet.2015.02.038

Cited by 12 publications

(19 citation statements)

References 46 publications

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“…Combination indices indicated synergism of the combinatorial treatment ( Supplementary Table S2 ). Therefore, considering our previous findings on the association of IGF-1R activation with primary vorinostat resistance (17), activation of the IGF-1R pathway appears to play a key role in both primary and acquired resistance to vorinostat and cross-resistance to other anticancer drugs in vorinostat-resistant sublines.…”

Section: Resultsmentioning

confidence: 80%

“…Recently, we reported that human NSCLC cell lines vary substantially in terms of their sensitivities to vorinostat (17). To investigate the molecular mechanisms underlying cancer resistance to vorinostat, three cell lines (H1944, H358, and H322) were subjected to in vitro selection processes using gradually increasing drug concentrations for 2-6 months.…”

Section: Resultsmentioning

confidence: 99%

“…These results were validated by the immunoblotting analyses of IGF-1R, Akt, ERK1/2 and their phosphorylated proteins ( Supplementary Figure S1B ). We previously demonstrated that IGF-1R activation contributes to primary resistance to HDAC inhibitors (17). We then assessed whether IGF-1R activation contributed to the acquired resistance to vorinostat.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, patients who initially respond to HDIs inevitably develop resistance; thus, identification of the possible mechanisms by which cancer cells develop acquired resistance to HDI-based therapy should be necessary. Our previous study indicated that HDIs, including vorinostat, activate the insulin-like growth factor 1 receptor (IGF-1R) signaling pathway in a subset of non-small cell lung cancers (NSCLC) with primary and acquired resistance to HDIs via direct binding of STAT3 to IGF2 P3 and P4 promoters, leading to increase in IGF2 transcription (17, 18). As a ligand for IGF-1R, IGF-2R, and insulin receptor isoform A (IR-A), IGF2 is known to modulate cell proliferation, survival, and differentiation (19).…”

Section: Introductionmentioning

confidence: 99%

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Essential Role of DNA Methyltransferase 1–mediated Transcription of Insulin-like Growth Factor 2 in Resistance to Histone Deacetylase Inhibitors

Min

Lee

Woo

et al. 2017

Clinical Cancer Research

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Purpose Histone deacetylase inhibitors (HDIs) are promising anticancer therapies; however, drug resistance limits their efficacy. Here, we investigated the molecular mechanisms underlying HDI resistance, focusing on the mechanism of HDI-mediated induction of insulin-like growth factor 2 (IGF2) based on our previous study. Experimental design The methylation status of CCCTC binding factor (CTCF)-binding sites in the IGF2/H19 imprinting control region (ICR) were determined by methylation-specific PCR and bisulfite sequencing. The effectiveness of single or combinatorial blockade of DNA methyltransferase 1 (DNMT1) and histone deacetylase (HDAC) was evaluated using cell viability assay and patient-derived tumor xenograft (PDX) model. Results HDAC inhibition by vorinostat increased acetylated STAT3 (K685), resulting in transcriptional upregulation of DNMT1. DNMT1-mediated hypermethylation of CTCF-binding sites in the IGF2/H19 ICR decreased CTCF insulator activity, leading to a transcriptional upregulation of IGF2 and activation of the insulin-like growth factor 1 receptor (IGF-1R) pathway in cells with acquired or de novo vorinostat resistance. Strategies targeting DNMT1 or STAT3 diminished the IGF2 expression and potentiated vorinostat sensitivity in preclinical models of lung cancer with hypermethylation in the H19/IGF2 ICR. The degree of ICR hypermethylation correlated with vorinostat resistance in patient-derived lung tumors and in patients with hematological malignancies. Conclusions DNMT1-mediated transcriptional upregulation of IGF2 is a novel mechanism of resistance to HDIs, highlighting the role of epigenetic deregulation of IGF2 in HDI resistance and the potential value of the H19/IGF2 ICR hypermethylation and DNMT1 expression as predictive biomarkers in HDI-based anticancer therapies.

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Section: Resultsmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Essential Role of DNA Methyltransferase 1–mediated Transcription of Insulin-like Growth Factor 2 in Resistance to Histone Deacetylase Inhibitors

Min

Lee

Woo

et al. 2017

Clinical Cancer Research

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“…Accordingly, IGF-1R was involved in resistance to EGFR-TKI in mutant KRAS NSCLC cells 16,25,37. Moreover, acetylation mechanisms regulated IGF-1R- and PI3K/AKT signaling,38,39 and the combination of an HDAC inhibitor with an EGFR-TKI inhibited AKT signaling in lung and head and neck cancer cells 9,14,16,33. It has also been reported that HDAC and EGFR co-inhibition modulated ErbB receptor levels but that these effects were independent of the EGFR or KRAS status 9,33.…”

Section: Discussionmentioning

confidence: 97%

Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma

Jeannot¹,

Busser²,

Vanwonterghem³

et al. 2016

OTT

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Development of drug resistance limits the efficacy of targeted therapies. Alternative approaches using different combinations of therapeutic agents to inhibit several pathways could be a more effective strategy for treating cancer. The effects of the approved epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (gefitinib) or a multi-targeted kinase inhibitor (sorafenib) in combination with a histone deacetylase inhibitor (vorinostat) on cell proliferation, cell cycle distribution, apoptosis, and signaling pathway activation in human lung adenocarcinoma and hepatocarcinoma cells with wild-type EGFR and mutant KRAS were investigated. The effects of the synergistic drug combinations were also studied in human lung adenocarcinoma and hepatocarcinoma cells in vivo. The combination of gefitinib and vorinostat synergistically reduced cell growth and strongly induced apoptosis through inhibition of the insulin-like growth factor-1 receptor/protein kinase B (IGF-1R/AKT)-dependent signaling pathway. Moreover, the gefitinib and vorinostat combination strongly inhibited tumor growth in mice with lung adenocarcinoma or hepatocarcinoma tumor xenografts. In contrast, the combination of sorafenib and vorinostat did not inhibit cell proliferation compared to a single treatment and induced G2/M cell cycle arrest without apoptosis. The sorafenib and vorinostat combination sustained the IGF-1R-, AKT-, and mitogen-activated protein kinase-dependent signaling pathways. These results showed that there was synergistic cytotoxicity when vorinostat was combined with gefitinib for both lung adenocarcinoma and hepatocarcinoma with mutant KRAS in vitro and in vivo but that the combination of vorinostat with sorafenib did not show any benefit. These findings highlight the important role of the IGF-1R/AKT pathway in the resistance to targeted therapies and support the use of histone deacetylase inhibitors in combination with EGFR-tyrosine kinase inhibitors, especially for treating patients with mutant KRAS resistant to other treatments.

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Establishment and characterization of BMC-PDC-019: a novel patient-derived cell line of EGFR-mutant pulmonary adenocarcinoma transformed into small-cell lung cancer

Kim,

Jung,

Hong

et al. 2023

Human Cell

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Activation of insulin-like growth factor receptor signaling mediates resistance to histone deacetylase inhibitors

Cited by 12 publications

References 46 publications

Essential Role of DNA Methyltransferase 1–mediated Transcription of Insulin-like Growth Factor 2 in Resistance to Histone Deacetylase Inhibitors

Essential Role of DNA Methyltransferase 1–mediated Transcription of Insulin-like Growth Factor 2 in Resistance to Histone Deacetylase Inhibitors

Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma

Establishment and characterization of BMC-PDC-019: a novel patient-derived cell line of EGFR-mutant pulmonary adenocarcinoma transformed into small-cell lung cancer

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