Combined Treatment with Silibinin and Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Overcomes Drug Resistance Caused by T790M Mutation

Rho, Jin Kyung; Choi, Yun Jung; Jeon, Byung-Suk; Choi, Su Jin; Cheon, Gi Jeong; Woo, Sang-Keun; Kim, Hye‐Ryoun; Kim, Cheol Hyeon; Choi, Chang‐Min; Lee, Jae Cheol

doi:10.1158/1535-7163.mct-10-0625

Cited by 44 publications

(33 citation statements)

References 36 publications

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“…Our results indicate that EGFR is a molecular target of DIM in ovarian cancer cells. Our results are in agreement with recent studies that showed that resveratrol, capsaicin, DIM, and silibinin suppress the growth of prostate, breast, and lung cancer cells by targeting EGFR (Stewart and O'Brian, 2004;Li et al, 2005;Ali et al, 2008;Rho et al, 2010;Thoennissen et al, 2010;Rajoria et al, 2011). Several pathways are affected by EGFR activation; MAPK is the main one.…”

Section: Discussionsupporting

confidence: 94%

Blocking Epidermal Growth Factor Receptor Activation by 3,3′-Diindolylmethane Suppresses Ovarian Tumor Growth In Vitro and In Vivo

Kandala¹,

Wright²,

Srivastava

2011

J Pharmacol Exp Ther

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Genetic alterations, including the overexpression of epidermal growth factor receptor (EGFR) (in approximately 70% of ovarian tumors), play a crucial role in the signal transduction pathways that regulate key cellular functions, such as cell survival and proliferation, and are responsible for compromising traditional chemotherapy. 3,3Ј-Diindolylmethane (DIM) is an indole compound present in Brassica vegetables. In our previous studies, we demonstrated that BR-DIM, a formulated version of DIM, suppressed the growth of ovarian cancer cells by causing cell cycle arrest and apoptosis. In the present study, we delineated the mechanism by which DIM suppressed the growth of SKOV-3, OVCAR-3, and TOV-21G human ovarian cancer cells. DIM treatment caused significant down-regulation of the constitutive EGFR protein level as well as phosphorylation of EGFR at Tyr1068, Tyr992, Tyr845, and Tyr1173 in various ovarian cancer cells. To determine whether DIM suppressed the activation of EGFR by activating phosphorylation, cells were treated with epidermal growth factor. Epidermal growth factor treatment significantly blocked the DIM-mediated inhibition of EGFR activation and apoptosis in both SKOV-3 and OVCAR-3 cells. In addition, DIM treatment drastically reduced the phosphorylation of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK), which are downstream to EGFR, without affecting their protein levels. DIM treatment also inhibited the kinase activity of ERK, as observed by the down-regulation of phospho-E twenty-six like transcription factor 1 (p-ELK1) in all three ovarian cancer cell lines. DIM significantly suppressed the growth of ovarian tumors in vivo. Tumor growth suppressive effects of DIM in SKOV-3 tumor xenografts were associated with reduced phosphorylation of EGFR, MEK, and ERK. These results indicate that DIM induces apoptosis in ovarian cancer cells by inhibiting the EGFR-ERK pathway in vitro and in vivo.

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Section: Discussionsupporting

confidence: 94%

Blocking Epidermal Growth Factor Receptor Activation by 3,3′-Diindolylmethane Suppresses Ovarian Tumor Growth In Vitro and In Vivo

Kandala¹,

Wright²,

Srivastava

2011

J Pharmacol Exp Ther

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“…We found that treatment with either agent was highly effective against multiple EGFR-mutant models in vitro (including PC9 and HCC827 cells with Del 19) (Figure 3A–B, Table S2). Moreover, GNS-1481 and GNS-1486 exhibited substantial efficacy in EGFR T790M -positive LA models in vitro , including PC-9/GR and PC-9/ER sub-lines with acquired resistance to gefitinib or erlotinib (33, 38), respectively, and H1975 cells that intrinsically harbor EGFR L858R/T790M (Figure 3A–B, Table S2). We further established the specificity of GNS-1481 and GNS-1486 efficacy for lung cancer cells with mutant EGFR by testing these agents in multiple EGFR WT lung cancer models, including A549, H460, and A341 cells.…”

Section: Resultsmentioning

confidence: 99%

Superior Efficacy and Selectivity of Novel Small-Molecule Kinase Inhibitors of T790M-Mutant EGFR in Preclinical Models of Lung Cancer

Rho

Lee²,

Choi

et al. 2017

Cancer Research

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The clinical utility of approved EGFR small molecule kinase inhibitors is plagued both by toxicity against wild-type EGFR and by metastatic progression in the central nervous system (CNS), a disease sanctuary site. Here we report the discovery and preclinical efficacy of GNS-1486 and GNS-1481, two novel small molecule EGFR kinase inhibitors that are selective for T790M mutant isoforms of EGFR. Both agents were effective in multiple mouse xenograft models of human lung adenocarcinoma (T790M positive or negative), exhibiting less activity against wild-type EGFR than existing approved EGFR kinase inhibitors (including osimertinib). Additionally, GNS-1486 showed superior potency against intracranial metastasis of EGFR-mutant lung adenocarcinoma. Our results offer a preclinical proof of concept for new EGFR kinase inhibitors with the potential to improve therapeutic index and efficacy against brain metastases in patients.

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“…In line with previous research, both H1975 and PC-9GR cells harbor T790M mutation and show a higher level of EGFR activity than H1299 cells expressing wild-type EGFR, regardless of the presence of ligand EGF. This differential effect between cells with mutant and wild-type EGFR might be related to the cellular dependency for survival to EGFR signaling (24). The inhibitory effect of E + G combination surmounted the threshold that the cancer cells could tolerate.…”

Section: Discussionmentioning

confidence: 99%

Combined Treatment withEpimedium koreanumNakai Extract and Gefitinib Overcomes Drug Resistance Caused by T790M Mutation in Non-Small Cell Lung Cancer Cells

Song

Zhong

Huang

et al. 2014

Nutrition and Cancer

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Although the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as gefitinib, have shown promising therapeutic efficacy in nonsmall cell lung cancer (NSCLC) patients harboring EGFR activating mutation, development of acquired resistance is almost inevitable. We investigated whether the addition of Epimedium koreanum Nakai extract (EEF) to gefitinib could overcome the resistance of NSCLC cells to gefitinib. In our study, the growth inhibitory effects of cotreatment differed between mutant EGFR and wild type EGFR. A synergistic antiproliferative effect was observed in the combined treatments in H1975 and PC-9GR cells carrying T790M EGFR. In addition, the cotreatment exhibited a much greater inhibition than either agent alone on the following metastatic processes: (a) invasion, (b) wound healing, and (c) tubule formation by endothelial cells. The phosphorylations of EGFR family (EGFR, HER-2, and HER-3) and EGFR downstream PI3K/Akt/mTOR pathway in H1975 and PC-9/GR cells were also attanuated, whereas EEF or gefitinib alone had no obvious effects. Similarly, the combination effectively suppressed tumor growth and increased mice survival in PC-9GR xenografts. The results indicate that the addition of EEF to gefitinib is a promising strategy to overcome T790M-mediated drug resistance.

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Combined Treatment with Silibinin and Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Overcomes Drug Resistance Caused by T790M Mutation

Cited by 44 publications

References 36 publications

Blocking Epidermal Growth Factor Receptor Activation by 3,3′-Diindolylmethane Suppresses Ovarian Tumor Growth In Vitro and In Vivo

Blocking Epidermal Growth Factor Receptor Activation by 3,3′-Diindolylmethane Suppresses Ovarian Tumor Growth In Vitro and In Vivo

Superior Efficacy and Selectivity of Novel Small-Molecule Kinase Inhibitors of T790M-Mutant EGFR in Preclinical Models of Lung Cancer

Combined Treatment withEpimedium koreanumNakai Extract and Gefitinib Overcomes Drug Resistance Caused by T790M Mutation in Non-Small Cell Lung Cancer Cells

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