γ Secretase Inhibitor BMS‐708163 Reverses Resistance to EGFR Inhibitor via the PI3K/Akt Pathway in Lung Cancer

Lung adenocarcinoma cells harboring epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitor (TKI). Acquired resistance to EGFR TKI develops after prolonged treatment. The aim of this study was to investigate the effect of the novel γ secretase inhibitor BMS‐708163 on acquired resistance to the EGFR TKI gefitinib. We did not observe known mechanisms of acquired resistance to EGFR TKI, including the EGFR T790M mutation and MET gene amplification in the gefitinib‐resistant PC9/AB2 cells. BMS‐708163 inhibited PI3K/Akt expression and sensitized PC9/AB2 cells to gefitinib‐induced cytotoxicity. In contrast, BMS‐708163 had no significant effect on gefitinib sensitivity in PC9 parental cells. Combined treatment with BMS‐708163 and gefitinib induced high levels of apoptosis. Our in vivo studies showed that combined treatment of gefitinib and BMS‐708163 inhibited the growth of PC9/AB2 xenografts. In conclusion, our data show that combined treatment of gefitinib and γ secretase inhibitors may be useful for treating lung adenocarcinomas harboring EGFR mutations with acquired gefitinib resistance. J. Cell. Biochem. 116: 1019–1027, 2015. © 2015 Wiley Periodicals, Inc.

[1]  M. He,et al.  Inhibition of the Jagged/Notch pathway inhibits retinoblastoma cell proliferation via suppressing the PI3K/Akt, Src, p38MAPK and Wnt/β‑catenin signaling pathways. , 2014, Molecular medicine reports.

[2]  S. Srivastava,et al.  Piperine Causes G1 Phase Cell Cycle Arrest and Apoptosis in Melanoma Cells through Checkpoint Kinase-1 Activation , 2014, PloS one.

[3]  K. Shilo,et al.  FAAH inhibition enhances anandamide mediated anti-tumorigenic effects in non-small cell lung cancer by downregulating the EGF/EGFR pathway , 2014, Oncotarget.

[4]  Sherry X. Yang,et al.  Targeting notch signaling pathway in cancer: clinical development advances and challenges. , 2014, Pharmacology & therapeutics.

[5]  Li Zhang,et al.  Notch-1 contributes to epidermal growth factor receptor tyrosine kinase inhibitor acquired resistance in non-small cell lung cancer in vitro and in vivo. , 2013, European journal of cancer.

[6]  K. Watabe,et al.  Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition , 2013, OncoTargets and therapy.

[7]  Yi-long Wu,et al.  Targeting mTOR to Overcome Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance in Non-Small Cell Lung Cancer Cells , 2013, PloS one.

[8]  K. Capaccione,et al.  The Notch signaling pathway as a mediator of tumor survival. , 2013, Carcinogenesis.

[9]  William Pao,et al.  Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR-Mutant Lung Cancers , 2013, Clinical Cancer Research.

[10]  C. Pereira,et al.  PCN17 Indirect Comparison of the Efficacy of Erlotinib Versus Pemetrexed Plus Cisplatin as First Line Treatment in Patients With Metastatic Non Small Cell Lung Cancer With Epidermal Growth Factor Receptor Activating Mutations , 2012 .

[11]  Gregory A. Wyant,et al.  Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy , 2012, Proceedings of the National Academy of Sciences.

[12]  Hongyun Zhao,et al.  Prognostic Significance of TAZ Expression in Resected Non-Small Cell Lung Cancer , 2012, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[13]  B. Bao,et al.  Notch-1 induces epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells. , 2011, Cancer letters.

[14]  Takayuki Kosaka,et al.  Mechanisms of Resistance to EGFR TKIs and Development of a New Generation of Drugs in Non-Small-Cell Lung Cancer , 2011, Journal of biomedicine & biotechnology.

[15]  Caicun Zhou,et al.  Integrin beta1 over‐expression associates with resistance to tyrosine kinase inhibitor gefitinib in non‐small cell lung cancer , 2010, Journal of cellular biochemistry.

[16]  Zhiwei Wang,et al.  Targeting Notch signaling pathway to overcome drug resistance for cancer therapy. , 2010, Biochimica et biophysica acta.

[17]  U. McDermott,et al.  Acquired resistance of non-small cell lung cancer cells to MET kinase inhibition is mediated by a switch to epidermal growth factor receptor dependency. , 2010, Cancer research.

[18]  Gregory J Riely,et al.  Impact of Epidermal Growth Factor Receptor and KRAS Mutations on Clinical Outcomes in Previously Untreated Non–Small Cell Lung Cancer Patients: Results of an Online Tumor Registry of Clinical Trials , 2009, Clinical Cancer Research.

[19]  S. Kobayashi,et al.  Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. , 2009, Clinical lung cancer.

[20]  A. Gilmore,et al.  Notch activation induces Akt signaling via an autocrine loop to prevent apoptosis in breast epithelial cells. , 2009, Cancer research.

[21]  Y. Yatabe,et al.  Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. , 2008, Cancer research.

[22]  T. Golde,et al.  ErbB-2 inhibition activates Notch-1 and sensitizes breast cancer cells to a γ-secretase inhibitor , 2008, Oncogene.

[23]  D. Yee,et al.  Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. , 2008, The Journal of clinical investigation.

[24]  William Pao,et al.  MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib , 2007, Proceedings of the National Academy of Sciences.

[25]  M. Rivera,et al.  Oncogenic activity of epidermal growth factor receptor kinase mutant alleles is enhanced by the T790M drug resistance mutation. , 2007, Cancer research.

[26]  L. L. Reed,et al.  Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi's sarcoma tumor cells , 2005, Oncogene.

[27]  N. Saijo,et al.  Establishment of a human non‐small cell lung cancer cell line resistant to gefitinib , 2005, International journal of cancer.

[28]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[29]  Hugo J. Bellen,et al.  Notch Signaling , 2014, Methods in Molecular Biology.

[30]  M. Huang,et al.  Cisplatin selects for multidrug-resistant CD133+ cells in lung adenocarcinoma by activating Notch signaling. , 2013, Cancer research.

[31]  T. Dang.  Notch, apoptosis and cancer. , 2012, Advances in experimental medicine and biology.

[32]  Mei Lan Tan,et al.  Apoptosis and Cancer , 2020, Cancer Immunology.