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
Biomedical Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 2049-9434 Online ISSN: 2049-9442
Journal Cover
April-2023 Volume 18 Issue 4

Full Size Image

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
April-2023 Volume 18 Issue 4

Full Size Image

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

Efficacy of PP121 in primary and metastatic non‑small cell lung cancers

  • Authors:
    • Quincy A. Quick
  • View Affiliations / Copyright

    Affiliations: Department of Biological Sciences, Tennessee State University, Nashville, TN 37209, USA
    Copyright: © Quick et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 29
    |
    Published online on: March 1, 2023
       https://doi.org/10.3892/br.2023.1611
  • 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

Tyrosine kinase inhibitors are a clinically standard treatment option for non‑small cell lung cancers (NSCLCs), the leading cause of cancer‑related deaths in the US. These targeted agents include first, second and third generation tyrosine kinase inhibitors; however, these lack clinical efficacy in the treatment of NSCLC due to intrinsic and acquired resistance. This resistance may be a result of genetic aberrations in oncogenic signaling mediators of divergent pathways. The present study aimed to investigate a novel dual tyrosine kinase and PI3K inhibitor, PP121, as a targeted agent in NSCLC cell lines. The present study co‑cultured PP121 with healthy human astrocytes, a prevalent cell type located in the brain of NSCLC brain metastases. To date, few preclinical studies have examined the efficacy of PP121 as an anticancer agent, and to the best of my knowledge, no previous studies have previously evaluated its therapeutic potential in the treatment of NSCLC. To investigate the clinical heterogeneity of NSCLC, patient‑derived adenocarcinoma (ADC) and squamous cell carcinoma (SCC) xenograft models were used, which exhibited epidermal growth factor receptor (EGFR) mutations and mesenchymal‑epithelial transition (MET) factor amplifications. Notably, both EGFR and MET are known contributors to tyrosine kinase inhibitor resistance; thus, the aforementioned mutations and amplifications enabled the effects of PP121 to be evaluated in these solid tumors. In addition, a co‑cultured model system using both NSCLC cells and astrocytes was employed to assess the effects of PP121 on the invasion of ADC and SCC cells in a multicellular environment. Results of the present study demonstrated that PP121 exerted an antitumorigenic effect in the aforementioned model systems via downregulation of pharmacodynamic targets.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

View References

1 

Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012.PubMed/NCBI View Article : Google Scholar

2 

Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013.PubMed/NCBI View Article : Google Scholar

3 

Yuan M, Huang LL, Chen JH, Wu J and Xu Q: The emerging treatment landscape of targeted therapy in non-small-cell lung cancer. Sig Transduct Target Ther. 4(61)2019.PubMed/NCBI View Article : Google Scholar

4 

König D, Savic Prince S and Rothschild SI: Targeted therapy in advanced and metastatic non-small cell lung cancer. An update on treatment of the most important actionable oncogenic driver alterations. Cancers (Basel). 13(804)2021.PubMed/NCBI View Article : Google Scholar

5 

Gazdar AF: Activating and resistance mutations of EGFR in non-small-cell lung cancer: Role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 28 (Suppl 1):S24–S31. 2009.PubMed/NCBI View Article : Google Scholar

6 

Clark J, Cools J and Gilliland DG: EGFR inhibition in non-small cell lung cancer: Resistance, once again, rears its ugly head. PLoS Med. 2(e75)2005.PubMed/NCBI View Article : Google Scholar

7 

Suda K, Murakami I, Katayama T, Tomizawa K, Osada H, Sekido Y, Maehara Y, Yatabe Y and Mitsudomi T: Reciprocal and complementary role of MET amplification and EGFR T790M mutation in acquired resistance to kinase inhibitors in lung cancer. Clin Cancer Res. 16:5489–5498. 2010.PubMed/NCBI View Article : Google Scholar

8 

Li F, Zhu T, Cao B, Wang J and Liang L: Apatinib enhances antitumour activity of EGFR-TKIs in non-small cell lung cancer with EGFR-TKI resistance. Eur J Cancer. 84:184–192. 2017.PubMed/NCBI View Article : Google Scholar

9 

Zhang Z, Zhang Y, Luo F, Ma Y, Fang W, Zhan J, Li S, Yang Y, Zhao Y, Hong S, et al: Dual blockade of EGFR and VEGFR pathways: Results from a pilot study evaluating apatinib plus gefitinib as a first-line treatment for advanced EGFR-mutant non-small cell lung cancer. Clin Transl Med. 10(e33)2020.PubMed/NCBI View Article : Google Scholar

10 

Benedettini E, Sholl LM, Peyton M, Reilly J, Ware C, Davis L, Vena N, Bailey D, Yeap BY, Fiorentino M, et al: Met activation in non-small cell lung cancer is associated with de novo resistance to EGFR inhibitors and the development of brain metastasis. Am J Pathol. 177:415–423. 2010.PubMed/NCBI View Article : Google Scholar

11 

Preusser M, Streubel B, Berghoff AS, Hainfellner JA, von Deimling A, Widhalm G, Dieckmann K, Wöhrer A, Hackl M, Zielinski C and Birner P: Amplification and overexpression of CMET is a common event in brain metastases of non-small cell lung cancer. Histopathology. 65:684–692. 2014.PubMed/NCBI View Article : Google Scholar

12 

Breindel JL, Haskins JW, Cowell EP, Zhao M, Nguyen DX and Stern DF: EGF receptor activates MET through MAPK to enhance non-small cell lung carcinoma invasion and brain metastasis. Cancer Res. 73:5053–5065. 2013.PubMed/NCBI View Article : Google Scholar

13 

Peng Y, Zhou Y, Cheng L, Hu D, Zhou X, Wang Z, Xie C and Zhou F: The anti-esophageal cancer cell activity by a novel tyrosine/phosphoinositide kinase inhibitor PP121. Biochem Biophys Res Commun. 465:137–144. 2015.PubMed/NCBI View Article : Google Scholar

14 

Apsel B, Blair JA, Gonzalez B, Nazif TM, Feldman ME, Aizenstein B, Hoffman R, Williams RL, Shokat KM and Knight ZA: Targeted polypharmacology: Discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat Chem Biol. 4:691–699. 2008.PubMed/NCBI View Article : Google Scholar

15 

Che HY, Guo HY, Si XW, You QY and Lou WY: PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, inhibits anaplastic thyroid carcinoma cell proliferation and migration. Tumour Biol. 35:8659–8664. 2014.PubMed/NCBI View Article : Google Scholar

16 

Kenny HA, Lal-Nag M, Shen M, Kara B, Nahotko DA, Wroblewski K, Fazal S, Chen S, Chiang CY, Chen YJ, et al: Quantitative high-throughput screening using an organotypic model identifies compounds that inhibit ovarian cancer metastasis. Mol Cancer Ther. 19:52–62. 2020.PubMed/NCBI View Article : Google Scholar

17 

Moore G, Lightner C, Elbai S, Brady L, Nicholson S, Ryan R, O'Sullivan KE, O'Byrne KJ, Blanco-Aparicio C, Cuffe S, et al: Co-Targeting PIM Kinase and PI3K/mTOR in NSCLC. Cancers (Basel). 13(2139)2021.PubMed/NCBI View Article : Google Scholar

18 

Montaudon E, El Botty R, Vacher S, Déas O, Naguez A, Chateau-Joubert S, Treguer D, de Plater L, Zemoura L, Némati F, et al: High in vitro and in vivo synergistic activity between mTORC1 and PLK1 inhibition in adenocarcinoma NSCLC. Oncotarget. 12:859–872. 2021.PubMed/NCBI View Article : Google Scholar

19 

Han J, Liu Y, Yang S, Wu X, Li H and Wang Q: MEK inhibitors for the treatment of non-small cell lung cancer. J Hematol Oncol. 14(1)2021.PubMed/NCBI View Article : Google Scholar

20 

Pérez-Tomás R: Multidrug resistance: Retrospect and prospects in anti-cancer drug treatment. Curr Med Chem. 13:1859–1876. 2006.PubMed/NCBI View Article : Google Scholar

21 

Chen KG, Valencia JC, Gillet JP, Hearing VJ and Gottesman MM: Involvement of ABC transporters in melanogenesis and the development of multidrug resistance of melanoma. Pigment Cell Melanoma Res. 22:740–749. 2009.PubMed/NCBI View Article : Google Scholar

22 

Chai AB, Callaghan R and Gelissen IC: Regulation of P-Glycoprotein in the Brain. Int J Mol Sci. 23(14667)2022.PubMed/NCBI View Article : Google Scholar

23 

Haar CP, Hebbar P, Wallace GC IV, Das A, Vandergrift WA III, Smith JA, Giglio P, Patel SJ, Ray SK and Banik NL: Drug resistance in glioblastoma: A mini review. Neurochem Res. 37:1192–1200. 2012.PubMed/NCBI View Article : Google Scholar

24 

Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, Chitale D, Motoi N, Szoke J, Broderick S, et al: MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA. 104:20932–20937. 2007.PubMed/NCBI View Article : Google Scholar

25 

Han B, Li K, Wang Q, Zhang L, Shi J, Wang Z, Cheng Y, He J, Shi Y, Zhao Y, et al: Effect of anlotinib as a third-line or further treatment on overall survival of patients with advanced non-small cell lung cancer: The ALTER 0303 phase 3 randomized clinical trial. JAMA Oncol. 4:1569–1575. 2018.PubMed/NCBI View Article : Google Scholar

26 

Zhang M, Quan H, Fu L, Li Y, Fu H and Lou L: Third-generation EGFR inhibitor HS-10296 in combination with famitinib, a multi-targeted tyrosine kinase inhibitor, exerts synergistic antitumor effects through enhanced inhibition of downstream signaling in EGFR-mutant non-small cell lung cancer cells. Thorac Cancer. 12:1210–1218. 2021.PubMed/NCBI View Article : Google Scholar

27 

Sun YW, Xu J, Zhou J and Liu WJ: Targeted drugs for systemic therapy of lung cancer with brain metastases. Oncotarget. 9:5459–5472. 2017.PubMed/NCBI View Article : Google Scholar

28 

Dai W, Zhu H, Chen G, Gu H, Gu Y, Sun X and Zeng X: Orchestration of the crosstalk between astrocytes and cancer cells affects the treatment and prognosis of lung cancer sufferers with brain metastasis. J Thorac Dis. 8:E1450–E1454. 2016.PubMed/NCBI View Article : Google Scholar

29 

Lin J, Jandial R, Nesbit A, Badie B and Chen M: Current and emerging treatments for brain metastases. Oncology (Williston Park). 29:250–257. 2015.PubMed/NCBI

30 

Ni W, Chen W and Lu Y: Emerging findings into molecular mechanism of brain metastasis. Cancer Med. 7:3820–3833. 2018.PubMed/NCBI View Article : Google Scholar

31 

Hanibuchi M, Kim SJ, Fidler IJ and Nishioka Y: The molecular biology of lung cancer brain metastasis: An overview of current comprehensions and future perspectives. J Med Invest. 61:241–253. 2014.PubMed/NCBI View Article : Google Scholar

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Quick QA: Efficacy of PP121 in primary and metastatic non‑small cell lung cancers. Biomed Rep 18: 29, 2023.
APA
Quick, Q.A. (2023). Efficacy of PP121 in primary and metastatic non‑small cell lung cancers. Biomedical Reports, 18, 29. https://doi.org/10.3892/br.2023.1611
MLA
Quick, Q. A."Efficacy of PP121 in primary and metastatic non‑small cell lung cancers". Biomedical Reports 18.4 (2023): 29.
Chicago
Quick, Q. A."Efficacy of PP121 in primary and metastatic non‑small cell lung cancers". Biomedical Reports 18, no. 4 (2023): 29. https://doi.org/10.3892/br.2023.1611
Copy and paste a formatted citation
x
Spandidos Publications style
Quick QA: Efficacy of PP121 in primary and metastatic non‑small cell lung cancers. Biomed Rep 18: 29, 2023.
APA
Quick, Q.A. (2023). Efficacy of PP121 in primary and metastatic non‑small cell lung cancers. Biomedical Reports, 18, 29. https://doi.org/10.3892/br.2023.1611
MLA
Quick, Q. A."Efficacy of PP121 in primary and metastatic non‑small cell lung cancers". Biomedical Reports 18.4 (2023): 29.
Chicago
Quick, Q. A."Efficacy of PP121 in primary and metastatic non‑small cell lung cancers". Biomedical Reports 18, no. 4 (2023): 29. https://doi.org/10.3892/br.2023.1611
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