Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
International Journal of Oncology
Join Editorial Board Propose a Special Issue
Print ISSN: 1019-6439 Online ISSN: 1791-2423
Journal Cover
February-2019 Volume 54 Issue 2

Full Size Image

Cover Legend PDF

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
February-2019 Volume 54 Issue 2

Full Size Image

Cover Legend PDF

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article Open Access

Targeting retinoblastoma protein phosphorylation in combination with EGFR inhibition in pancreatic cancer cells

  • Authors:
    • Nimmi A. Thomas
    • Rita G. Abraham
    • Brixhilda Dedi
    • Nancy A. Krucher
  • View Affiliations / Copyright

    Affiliations: Department of Biology, Pace University, Pleasantville, NY 10570, USA
    Copyright: © Thomas et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 527-536
    |
    Published online on: December 7, 2018
       https://doi.org/10.3892/ijo.2018.4658
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a particularly lethal disease that is resistant to targeted therapies. Tyrosine kinase inhibitors (TKIs), including erlotinib and gefitinib, which block the action of the human epidermal growth factor receptor type 1 receptor, provide small increases in patient survival when administered with gemcitabine. The retinoblastoma (Rb) tumor suppressor protein is an additional target in pancreatic cancer, due to its documented inactivation in PDAC. The present study, using cell number, apoptosis and immunoblotting assays, aimed to evaluate the effects of activation of the Rb tumor suppressor via dephosphorylation by small interfering RNA‑mediated phosphatase activation. In the Panc1, MIAPaCa‑2 and Capan‑2 pancreatic cancer cell lines, and in normal H6c7 cells, the effects of phosphatase activation on Rb were revealed to be dependent on expression of the p16 tumor suppressor, which regulates Rb phosphorylation. Phosphatase activation had no effect on non‑transformed pancreatic epithelial cells. When comparing kinase inhibition with phosphatase activation, it was demonstrated that kinase inhibition reduced proliferation, whereas phosphatase activation induced apoptosis. Both treatments together resulted in a greater reduction of pancreatic cancer cells than either treatment alone. In addition, the effects of combination treatment of phosphatase activation with TKIs on cell number and activation of the signal transducer and activator of transcription 3 (STAT3) resistance pathway were determined. The combination of Rb phosphatase activation with TKIs resulted in a greater reduction in cell number compared with either treatment alone, without STAT3 pathway activation. These data suggested that targeting Rb phosphorylation by activating phosphatase may be a rational strategy to inhibit pancreatic tumor cell growth, without activation of acquired resistance.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

View References

1 

Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar

2 

Ryan DP, Hong TS and Bardeesy N: Pancreatic adenocarcinoma. N Engl J Med. 371:1039–1049. 2014. View Article : Google Scholar

3 

Philip PA and Lutz MP: Targeting Epidermal Growth factor receptor-related signaling pathways in pancreatic cancer. Pancreas. 44:1046–1052. 2015. View Article : Google Scholar

4 

Yang ZY, Yuan JQ, Di MY, Zheng DY, Chen JZ, Ding H, Wu XY, Huang YF, Mao C and Tang JL: Gemcitabine plus erlotinib for advanced pancreatic cancer: A systematic review with meta-analysis. PLoS One. 8:e575282013. View Article : Google Scholar :

5 

Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, et al: National Cancer Institute of Canada Clinical Trials Group: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 25:1960–1966. 2007. View Article : Google Scholar

6 

Troiani T1, Martinelli E, Capasso A, Morgillo F, Orditura M, De Vita F and Ciardiello F: Targeting EGFR in pancreatic cancer treatment. Curr Drug Targets. 13:802–810. 2012. View Article : Google Scholar

7 

Nedaeinia R, Avan A, Manian M, Salehi R and Ghayour- Mobarhan M: EGFR as a potential target for the treatment of pancreatic cancer: Dilemma and controversies. Curr Drug Targets. 15:1293–1301. 2014. View Article : Google Scholar

8 

Zhao C, Li H, Lin HJ, Yang S, Lin J and Liang G: Feedback activation of STAT3 as a cancer drug-resistance mechanism. Trends Pharmacol Sci. 37:47–61. 2016. View Article : Google Scholar

9 

Lee H-J, Zhuang G, Cao Y, Du P, Kim HJ and Settleman J: Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell. 26:207–221. 2014. View Article : Google Scholar

10 

Ioannou N, Seddon AM, Dalgleish A, Mackintosh D, Solca F and Modjtahedi H: Acquired resistance of pancreatic cancer cells to treatment with gemcitabine and HER-inhibitors is accompanied by increased sensitivity to STAT3 inhibition. Int J Oncol. 48:908–918. 2016. View Article : Google Scholar : PubMed/NCBI

11 

Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK, Moskaluk CA, Hahn SA, Schwarte-Waldhoff I, Schmiegel W, et al: Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res. 57:3126–3130. 1997.

12 

Hustinx SR, Leoni LM, Yeo CJ, Brown PN, Goggins M, Kern SE, Hruban RH and Maitra A: Concordant loss of MTAP and p16/CDKN2A expression in pancreatic intraepithelial neoplasia: Evidence of homozygous deletion in a noninvasive precursor lesion. Mod Pathol. 18:959–963. 2005. View Article : Google Scholar

13 

Fukushima N, Sato N, Ueki T, Rosty C, Walter KM, Wilentz RE, Yeo CJ, Hruban RH and Goggins M: Aberrant methylation of preproenkephalin and p16 genes in pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma. Am J Pathol. 160:1573–1581. 2002. View Article : Google Scholar

14 

Gerdes B, Ramaswamy A, Kersting M, Ernst M, Lang S, Schuermann M, Wild A and Bartsch DK: p16(INK4a) alterations in chronic pancreatitis-indicator for high-risk lesions for pancreatic cancer. Surgery. 129:490–497. 2001. View Article : Google Scholar

15 

Makohon-Moore A and Iacobuzio-Donahue CA: Pancreatic cancer biology and genetics from an evolutionary perspective. Nat Rev Cancer. 16:553–565. 2016. View Article : Google Scholar : PubMed/NCBI

16 

Notta F, Chan-Seng-Yue M, Lemire M, Li Y, Wilson GW, Connor AA, Denroche RE, Liang SB, Brown AM, Kim JC, et al: A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature. 538:378–382. 2016. View Article : Google Scholar : PubMed/NCBI

17 

Rabien A, Sanchez-Ruderisch H, Schulz P, Otto N, Wimmel A, Wiedenmann B and Detjen KM: Tumor suppressor p16INK4a controls oncogenic K-Ras function in human pancreatic cancer cells. Cancer Sci. 103:169–175. 2012. View Article : Google Scholar

18 

Chang Z, Ju H, Ling J, Zhuang Z, Li Z, Wang H, Fleming JB, Freeman JW, Yu D, Huang P, et al: Cooperativity of oncogenic K-ras and downregulated p16/INK4A in human pancreatic tumorigenesis. PLoS One. 9:e1014522014. View Article : Google Scholar :

19 

Li J, Poi MJ and Tsai MD: Regulatory mechanisms of tumor suppressor P16(INK4A) and their relevance to cancer. Biochemistry. 50:5566–5582. 2011. View Article : Google Scholar

20 

Franco J, Witkiewicz AK and Knudsen ES: CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer. Oncotarget. 5:6512–6525. 2014. View Article : Google Scholar

21 

Heilmann AM, Perera RM, Ecker V, Nicolay BN, Bardeesy N, Benes CH and Dyson NJ: CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16INK4A-deficient pancreatic cancers. Cancer Res. 74:3947–3958. 2014. View Article : Google Scholar

22 

Liu F and Korc M: Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 11:2138–2148. 2012. View Article : Google Scholar

23 

Witkiewicz AK, Borja NA, Franco J, Brody JR, Yeo CJ, Mansour J, Choti MA, McCue P and Knudsen ES: Selective impact of CDK4/6 suppression on patient-derived models of pancreatic cancer. Oncotarget. 6:15788–15801. 2015. View Article : Google Scholar

24 

Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, Harbeck N, Lipatov ON, Walshe JM, Moulder S, et al: Palbociclib and Letrozole in advanced breast cancer. N Engl J Med. 375:1925–1936. 2016. View Article : Google Scholar : PubMed/NCBI

25 

Nelson DA, Krucher NA and Ludlow JW: High molecular weight protein phosphatase type 1 dephosphorylates the retinoblastoma protein. J Biol Chem. 272:4528–4535. 1997. View Article : Google Scholar

26 

Bollen M, Peti W, Ragusa MJ and Beullens M: The extended PP1 toolkit: Designed to create specificity. Trends Biochem Sci. 33:113–121. 2003.

27 

Kolupaeva V and Janssens V: PP1 and PP2A phosphatases - cooperating partners in modulating retinoblastoma protein activation. FEBS J. 280:627–643. 2013. View Article : Google Scholar

28 

Allen PB, Kwon YG, Nairn AC and Greengard P: Isolation and characterization of PNUTS, a putative protein phosphatase 1 nuclear targeting subunit. J Biol Chem. 273:4089–4095. 1998. View Article : Google Scholar : PubMed/NCBI

29 

Kreivi JP, Trinkle-Mulcahy L, Lyon CE, Morrice NA, Cohen P and Lamond AI: Purification and characterisation of p99, a nuclear modulator of protein phosphatase 1 activity. FEBS Lett. 420:57–62. 1997. View Article : Google Scholar

30 

Udho E, Tedesco VC, Zygmunt A and Krucher NA: PNUTS (phosphatase nuclear targeting subunit) inhibits retinoblastoma-directed PP1 activity. Biochem Biophys Res Commun. 297:463–467. 2002. View Article : Google Scholar

31 

Choy MS, Hieke M, Kumar GS, Lewis GR, Gonzalez-DeWhitt KR, Kessler RP, Stein BJ, Hessenberger M, Nairn AC, Peti W, et al: Understanding the antagonism of retinoblastoma protein dephosphorylation by PNUTS provides insights into the PP1 regulatory code. Proc Natl Acad Sci USA. 111:4097–4102. 2014. View Article : Google Scholar : PubMed/NCBI

32 

Hoekstra E, Peppelenbosch MP and Fuhler GM: Meeting report Europhosphatase 2015: Phosphatases as drug targets in cancer. Cancer Res. 76:193–196. 2016. View Article : Google Scholar

33 

Kim YM, Watanabe T, Allen PB, Kim YM, Lee SJ, Greengard P, Nairn AC and Kwon YG: PNUTS, a protein phosphatase 1 (PP1) nuclear targeting subunit. Characterization of its PP1- and RNA-binding domains and regulation by phosphorylation. J Biol Chem. 278:13819–13828. 2003. View Article : Google Scholar

34 

Krucher NA, Rubin E, Tedesco VC, Roberts MH, Sherry TC and De Leon G: Dephosphorylation of Rb (Thr-821) in response to cell stress. Exp Cell Res. 312:2757–2763. 2006. View Article : Google Scholar

35 

De Leon G, Sherry TC and Krucher NA: Reduced expression of PNUTS leads to activation of Rb-phosphatase and caspase- mediated apoptosis. Cancer Biol Ther. 7:833–841. 2008. View Article : Google Scholar

36 

Kavela S, Shinde SR, Ratheesh R, Viswakalyan K, Bashyam MD, Gowrishankar S, Vamsy M, Pattnaik S, Rao S, Sastry RA, et al: PNUTS functions as a proto-oncogene by sequestering PTEN. Cancer Res. 73:205–214. 2013. View Article : Google Scholar

37 

Egger JV, Lane MV, Antonucci LA, Dedi B and Krucher NA: Dephosphorylation of the Retinoblastoma protein (Rb) inhibits cancer cell EMT via Zeb. Cancer Biol Ther. 17:1197–1205. 2016. View Article : Google Scholar : PubMed/NCBI

38 

Pino MS, Shrader M, Baker CH, Cognetti F, Xiong HQ, Abbruzzese JL and McConkey DJ: Transforming growth factor alpha expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines. Cancer Res. 66:3802–3812. 2006. View Article : Google Scholar

39 

Buck E, Eyzaguirre A, Haley JD, Gibson NW, Cagnoni P and Iwata KK: Inactivation of Akt by the epidermal growth factor receptor inhibitor erlotinib is mediated by HER-3 in pancreatic and colorectal tumor cell lines and contributes to erlotinib sensitivity. Mol Cancer Ther. 5:2051–2059. 2006. View Article : Google Scholar

40 

Ali S, Banerjee S, Ahmad A, El-Rayes BF, Philip PA and Sarkar FH: Apoptosis-inducing effect of erlotinib is potentiated by 3,3'-diindolylmethane in vitro and in vivo using an orthotopic model of pancreatic cancer. Mol Cancer Ther. 7:1708–1719. 2008. View Article : Google Scholar

41 

Deer EL, Gonzalez-Hernandez J, Coursen JD, Shea JE, Ngatia J, Scaife CL, Firpo MA and Mulvihill SJ: Phenotype and genotype of pancreatic cancer cell lines. Pancreas. 39:425–435. 2010. View Article : Google Scholar :

42 

Gradiz R, Silva HC, Carvalho L, Botelho MF and Mota-Pinto A: MIA PaCa-2 and PANC-1 - pancreas ductal adenocarcinoma cell lines with neuroendocrine differentiation and somatostatin receptors. Sci Rep. 6:216482016. View Article : Google Scholar

43 

Loukopoulos P, Kanetaka K, Takamura M, Shibata T, Sakamoto M and Hirohashi S: Orthotopic transplantation models of pancreatic adenocarcinoma derived from cell lines and primary tumors and displaying varying metastatic activity. Pancreas. 29:193–203. 2004. View Article : Google Scholar : PubMed/NCBI

44 

Furukawa T, Duguid WP, Rosenberg L, Viallet J, Galloway DA and Tsao MS: Long-term culture and immortalization of epithelial cells from normal adult human pancreatic ducts transfected by the E6E7 gene of human papilloma virus 16. Am J Pathol. 148:1763–1770. 1996.PubMed/NCBI

45 

Macdonald JI and Dick FA: Posttranslational modifications of the retinoblastoma tumor suppressor protein as determinants of function. Genes Cancer. 3:619–633. 2012. View Article : Google Scholar

46 

De Leon G, Cavino M, D'Angelo M and Krucher NA: PNUTS knockdown potentiates the apoptotic effect of Roscovitine in breast and colon cancer cells. Int J Oncol. 36:1269–1275. 2010.PubMed/NCBI

47 

Mohammed A, Janakiram NB, Li Q, Madka V, Ely M, Lightfoot S, Crawford H, Steele VE and Rao CV: EGFR inhibitor gefitinib prevents progression of pancreatic lesions to carcinoma in a conditional LSL-KrasG12D/+ transgenic mice model. Cancer Prev Res (Phila). 3:1417–1426. 2010. View Article : Google Scholar

48 

Lin Y, Wang X and Jin H: EGFR-TKI resistance in NSCLC patients: Mechanisms and strategies. Am J Cancer Res. 4:411–435. 2014.

49 

Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science. 304:1497–1500. 2004. View Article : Google Scholar

50 

Jackman D, Pao W, Riely GJ, Engelman JA, Kris MG, Jänne PA, Lynch T, Johnson BE and Miller VA: Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol. 28:357–360. 2010. View Article : Google Scholar

51 

Scholz A, Heinze S, Detjen KM, Peters M, Welzel M, Hauff P, Schirner M, Wiedenmann B and Rosewicz S: Activated signal transducer and activator of transcription 3 (STAT3) supports the malignant phenotype of human pancreatic cancer. Gastroenterology. 125:891–905. 2003. View Article : Google Scholar

52 

Toyonaga T, Nakano K, Nagano M, Zhao G, Yamaguchi K, Kuroki S, Eguchi T, Chijiiwa K, Tsuneyoshi M and Tanaka M: Blockade of constitutively activated Janus kinase/signal transducer and activator of transcription-3 pathway inhibits growth of human pancreatic cancer. Cancer Lett. 201:107–116. 2003. View Article : Google Scholar

53 

Corcoran RB, Contino G, Deshpande V, Tzatsos A, Conrad C, Benes CH, Levy DE, Settleman J, Engelman JA and Bardeesy N: STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res. 71:5020–5029. 2011. View Article : Google Scholar : PubMed/NCBI

54 

Fofaria NM and Srivastava SK: STAT3 induces anoikis resistance, promotes cell invasion and metastatic potential in pancreatic cancer cells. Carcinogenesis. 36:142–150. 2015. View Article : Google Scholar

55 

Wu X, Tang W, Marquez RT, Li K, Highfill CA, He F, Lian J, Lin J, Fuchs JR, Ji M, et al: Overcoming chemo/radio-resistance of pancreatic cancer by inhibiting STAT3 signaling. Oncotarget. 7:11708–11723. 2016.

56 

Zhang X, Ren D, Wu X, Lin X, Ye L, Lin C, Wu S, Zhu J, Peng X and Song L: miR-1266 contributes to pancreatic cancer progression and chemoresistance by the STAT3 and NF-kB signaling pathways. Mol Ther Nucleic Acids. 11:142–158. 2018. View Article : Google Scholar

57 

Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, Ginther C, Atefi M, Chen I, Fowst C, et al: PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 11:R772009. View Article : Google Scholar

58 

Dean JL, Thangavel C, McClendon AK, Reed CA and Knudsen ES: Therapeutic CDK4/6 inhibition in breast cancer: Key mechanisms of response and failure. Oncogene. 29:4018–4032. 2010. View Article : Google Scholar

59 

Yang C, Li Z, Bhatt T, Dickler M, Giri D, Scaltriti M, Baselga J, Rosen N and Chandarlapaty S: Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence. Oncogene. 36:2255–2264. 2017. View Article : Google Scholar

60 

Guri Y and Hall MN: mTOR signaling confers resistance to targeted cancer drugs. Trends Cancer. 2:688–697. 2016. View Article : Google Scholar

61 

Franco J, Balaji U, Freinkman E, Witkiewicz AK and Knudsen ES: Metabolic reprogramming of pancreatic cancer mediated by CDK4/6 inhibition elicits unique vulnerabilities. Cell Rep. 14:979–990. 2016. View Article : Google Scholar : PubMed/NCBI

62 

Zhang J, Xu K, Liu P, Geng Y, Wang B, Gan W, Guo J, Wu F, Chin YR, Berrios C, et al: Inhibition of Rb phosphorylation leads to mTORC2 mediated activation of AKT. Mol Cell. 62:929–942. 2016. View Article : Google Scholar

63 

Arumugam T, Ramachandran V, Fournier KF, Wang H, Marquis L, Abbruzzese JL, Gallick GE, Logsdon CD, McConkey DJ and Choi W: Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 69:5820–5828. 2009. View Article : Google Scholar : PubMed/NCBI

64 

Sherr CJ: Cancer cell cycles. Science. 274:1672–1677. 1996. View Article : Google Scholar

65 

Mittnacht S: The retinoblastoma protein--from bench to bedside. Eur J Cell Biol. 84:97–107. 2005. View Article : Google Scholar

66 

Sherr CJ and McCormick F: The RB and p53 pathways in cancer. Cancer Cell. 2:103–112. 2002. View Article : Google Scholar : PubMed/NCBI

67 

Harbour JW and Dean DC: The Rb/E2F pathway: Expanding roles and emerging paradigms. Genes Dev. 14:2393–2409. 2000. View Article : Google Scholar

68 

Thangavel C, Boopathi E, Liu Y, Haber A, Ertel A, Bhardwaj A, Addya S, Williams N, Ciment SJ, Cotzia P, et al: RB loss promotes prostate cancer metastasis. Cancer Res. 77:982–995. 2017. View Article : Google Scholar :

69 

Arima Y, Hayashi H, Sasaki M, Hosonaga M, Goto TM, Chiyoda T, Kuninaka S, Shibata T, Ohata H, Nakagama H, et al: Induction of ZEB proteins by inactivation of RB protein is key determinant of mesenchymal phenotype of breast cancer. J Biol Chem. 287:7896–7906. 2012. View Article : Google Scholar

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Thomas NA, Abraham RG, Dedi B and Krucher NA: Targeting retinoblastoma protein phosphorylation in combination with EGFR inhibition in pancreatic cancer cells. Int J Oncol 54: 527-536, 2019.
APA
Thomas, N.A., Abraham, R.G., Dedi, B., & Krucher, N.A. (2019). Targeting retinoblastoma protein phosphorylation in combination with EGFR inhibition in pancreatic cancer cells. International Journal of Oncology, 54, 527-536. https://doi.org/10.3892/ijo.2018.4658
MLA
Thomas, N. A., Abraham, R. G., Dedi, B., Krucher, N. A."Targeting retinoblastoma protein phosphorylation in combination with EGFR inhibition in pancreatic cancer cells". International Journal of Oncology 54.2 (2019): 527-536.
Chicago
Thomas, N. A., Abraham, R. G., Dedi, B., Krucher, N. A."Targeting retinoblastoma protein phosphorylation in combination with EGFR inhibition in pancreatic cancer cells". International Journal of Oncology 54, no. 2 (2019): 527-536. https://doi.org/10.3892/ijo.2018.4658
Copy and paste a formatted citation
x
Spandidos Publications style
Thomas NA, Abraham RG, Dedi B and Krucher NA: Targeting retinoblastoma protein phosphorylation in combination with EGFR inhibition in pancreatic cancer cells. Int J Oncol 54: 527-536, 2019.
APA
Thomas, N.A., Abraham, R.G., Dedi, B., & Krucher, N.A. (2019). Targeting retinoblastoma protein phosphorylation in combination with EGFR inhibition in pancreatic cancer cells. International Journal of Oncology, 54, 527-536. https://doi.org/10.3892/ijo.2018.4658
MLA
Thomas, N. A., Abraham, R. G., Dedi, B., Krucher, N. A."Targeting retinoblastoma protein phosphorylation in combination with EGFR inhibition in pancreatic cancer cells". International Journal of Oncology 54.2 (2019): 527-536.
Chicago
Thomas, N. A., Abraham, R. G., Dedi, B., Krucher, N. A."Targeting retinoblastoma protein phosphorylation in combination with EGFR inhibition in pancreatic cancer cells". International Journal of Oncology 54, no. 2 (2019): 527-536. https://doi.org/10.3892/ijo.2018.4658
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team