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
September-2016 Volume 49 Issue 3

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
September-2016 Volume 49 Issue 3

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

Targeting the PI3K/AKT/mTOR pathway overcomes the stimulating effect of dabrafenib on the invasive behavior of melanoma cells with acquired resistance to the BRAF inhibitor

  • Authors:
    • Simona Caporali
    • Ester Alvino
    • Pedro Miguel Lacal
    • Lauretta Levati
    • Giorgio Giurato
    • Domenico Memoli
    • Elisabetta Caprini
    • Gian Carlo Antonini Cappellini
    • Stefania D'Atri
  • View Affiliations / Copyright

    Affiliations: Laboratory of Molecular Oncology, Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy, Institute of Translational Pharmacology, National Council of Research, Rome, Italy, Laboratory of Molecular Medicine and Genomics, University of Salerno, Baronissi (SA), Italy, Department of Oncology and Dermatological Oncology, Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy
  • Pages: 1164-1174
    |
    Published online on: June 30, 2016
       https://doi.org/10.3892/ijo.2016.3594
  • 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

BRAF inhibitors (BRAFi) have proven clinical benefits in patients with BRAF-mutant melanoma. However, acquired resistance eventually arises. The effects of BRAFi on melanoma cell proliferation and survival have been extensively studied, and several mechanisms involved in acquired resistance to the growth suppressive activity of these drugs have been identified. Much less is known about the impact of BRAFi, and in particular of dabrafenib, on the invasive potential of melanoma cells. In the present study, the BRAF-mutant human melanoma cell line A375 and its dabrafenib-resistant subline A375R were analyzed for invasive capacity, expression of vascular endothelial growth factor receptor (VEGFR)-2, and secretion of VEGF-A and matrix metalloproteinase (MMP)-9, under basal conditions or in response to dabrafenib. The consequences of inhibiting the PI3K/AKT/mTOR pathway on A375R cell responses to dabrafenib were also evaluated. We found that A375R cells were more invasive and secreted higher levels of VEGF-A and MMP-9 as compared with A375 cells. Dabrafenib reduced invasiveness, VEGFR-2 expression and VEGF-A secretion in A375 cells, whereas it increased invasiveness, VEGF-A and MMP-9 release in A375R cells. In these latter cells, the stimulating effects of dabrafenib on the invasive capacity were markedly impaired by the anti-VEGF‑A antibody bevacizumab, or by AKT1 silencing. A375R cells were not cross-resistant to the PI3K/mTOR inhibitor GSK2126458A. Moreover, this inhibitor given in combination with dabrafenib efficiently counteracted the stimulating effects of the BRAFi on invasiveness and VEGF-A and MMP-9 secretion. Our data demonstrate that melanoma cells with acquired resistance to dabrafenib possess a more invasive phenotype which is further stimulated by exposure to the drug. Substantial evidence indicates that continuing BRAFi therapy beyond progression produces a clinical benefit. Our results suggest that after the development of resistance, a regimen combining BRAFi with bevacizumab or with inhibitors of the PI3K/AKT/mTOR pathway might be more effective than BRAFi monotherapy.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

View References

1 

Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, et al: Mutations of the BRAF gene in human cancer. Nature. 417:949–954. 2002. View Article : Google Scholar : PubMed/NCBI

2 

Lopez-Bergami P: The role of mitogen- and stress-activated protein kinase pathways in melanoma. Pigment Cell Melanoma Res. 24:902–921. 2011. View Article : Google Scholar : PubMed/NCBI

3 

Sullivan RJ and Flaherty K: MAP kinase signaling and inhibition in melanoma. Oncogene. 32:2373–2379. 2013. View Article : Google Scholar

4 

Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, et al; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 364:2507–2516. 2011. View Article : Google Scholar : PubMed/NCBI

5 

Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, et al; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 367:107–114. 2012. View Article : Google Scholar : PubMed/NCBI

6 

Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, et al: Dabrafenib in BRAF-mutated metastatic melanoma: A multicentre, open-label, phase 3 randomised controlled trial. Lancet. 380:358–365. 2012. View Article : Google Scholar : PubMed/NCBI

7 

Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, et al: Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 367:1694–1703. 2012. View Article : Google Scholar : PubMed/NCBI

8 

Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, et al: Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 372:30–39. 2015. View Article : Google Scholar

9 

Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, et al: Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: A multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 386:444–451. 2015. View Article : Google Scholar : PubMed/NCBI

10 

Sullivan RJ and Flaherty KT: Resistance to BRAF-targeted therapy in melanoma. Eur J Cancer. 49:1297–1304. 2013. View Article : Google Scholar : PubMed/NCBI

11 

Holderfield M, Deuker MM, McCormick F and McMahon M: Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. Nat Rev Cancer. 14:455–467. 2014. View Article : Google Scholar : PubMed/NCBI

12 

Fedorenko IV, Gibney GT, Sondak VK and Smalley KSM: Beyond BRAF: Where next for melanoma therapy? Br J Cancer. 112:217–226. 2015. View Article : Google Scholar :

13 

Spagnolo F, Ghiorzo P, Orgiano L, Pastorino L, Picasso V, Tornari E, Ottaviano V and Queirolo P: BRAF-mutant melanoma: Treatment approaches, resistance mechanisms, and diagnostic strategies. Onco Targets Ther. 8:157–168. 2015. View Article : Google Scholar : PubMed/NCBI

14 

Yadav V, Zhang X, Liu J, Estrem S, Li S, Gong XQ, Buchanan S, Henry JR, Starling JJ and Peng SB: Reactivation of mitogen-activated protein kinase (MAPK) pathway by FGF receptor 3 (FGFR3)/Ras mediates resistance to vemurafenib in human B-RAF V600E mutant melanoma. J Biol Chem. 287:28087–28098. 2012. View Article : Google Scholar : PubMed/NCBI

15 

Sabbatino F, Wang Y, Wang X, Flaherty KT, Yu L, Pepin D, Scognamiglio G, Pepe S, Kirkwood JM, Cooper ZA, et al: PDGFRα up-regulation mediated by sonic hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation. Oncotarget. 5:1926–1941. 2014. View Article : Google Scholar : PubMed/NCBI

16 

Wang J, Huang SK, Marzese DM, Hsu SC, Kawas NP, Chong KK, Long GV, Menzies AM, Scolyer RA, Izraely S, et al: Epigenetic changes of EGFR have an important role in BRAF inhibitor-resistant cutaneous melanomas. J Invest Dermatol. 135:532–541. 2015. View Article : Google Scholar

17 

Halaban R, Zhang W, Bacchiocchi A, Cheng E, Parisi F, Ariyan S, Krauthammer M, McCusker JP, Kluger Y and Sznol M: PLX4032, a selective BRAFV600E kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells. Pigment Cell Melanoma Res. 23:190–200. 2010. View Article : Google Scholar : PubMed/NCBI

18 

Girotti MR, Pedersen M, Sanchez-Laorden B, Viros A, Turajlic S, Niculescu-Duvaz D, Zambon A, Sinclair J, Hayes A, Gore M, et al: Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma. Cancer Discov. 3:158–167. 2013. View Article : Google Scholar

19 

Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Bremer R, Gillette S, Kong J, Haass NK, et al: Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci USA. 105:3041–3046. 2008. View Article : Google Scholar : PubMed/NCBI

20 

Vultur A, Villanueva J, Krepler C, Rajan G, Chen Q, Xiao M, Li L, Gimotty PA, Wilson M, Hayden J, et al: MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines. Oncogene. 33:1850–1861. 2014. View Article : Google Scholar

21 

Zubrilov I, Sagi-Assif O, Izraely S, Meshel T, Ben-Menahem S, Ginat R, Pasmanik-Chor M, Nahmias C, Couraud PO, Hoon DSB, et al: Vemurafenib resistance selects for highly malignant brain and lung-metastasizing melanoma cells. Cancer Lett. 361:86–96. 2015. View Article : Google Scholar : PubMed/NCBI

22 

Sanchez-Laorden B, Viros A, Girotti MR, Pedersen M, Saturno G, Zambon A, Niculescu-Duvaz D, Turajlic S, Hayes A, Gore M, et al: BRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by reactivating MEK and ERK signaling. Sci Signal. 7:ra302014. View Article : Google Scholar : PubMed/NCBI

23 

Vergani E, Vallacchi V, Frigerio S, Deho P, Mondellini P, Perego P, Cassinelli G, Lanzi C, Testi MA, Rivoltini L, et al: Identification of MET and SRC activation in melanoma cell lines showing primary resistance to PLX4032. Neoplasia. 13:1132–1142. 2011. View Article : Google Scholar

24 

Li H and Durbin R: Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 25:1754–1760. 2009. View Article : Google Scholar : PubMed/NCBI

25 

McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, et al: The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20:1297–1303. 2010. View Article : Google Scholar : PubMed/NCBI

26 

Yang H and Wang K: Genomic variant annotation and prioritization with ANNOVAR and wANNOVAR. Nat Protoc. 10:1556–1566. 2015. View Article : Google Scholar : PubMed/NCBI

27 

Pepponi R, Marra G, Fuggetta MP, Falcinelli S, Pagani E, Bonmassar E, Jiricny J and D’Atri S: The effect of O6-alkylguanine-DNA alkyltransferase and mismatch repair activities on the sensitivity of human melanoma cells to temozolomide, 1,3-bis(2-chloroethyl)1-nitrosourea, and cisplatin. J Pharmacol Exp Ther. 304:661–668. 2003. View Article : Google Scholar : PubMed/NCBI

28 

Caporali S, Falcinelli S, Starace G, Russo MT, Bonmassar E, Jiricny J and D’Atri S: DNA damage induced by temozolomide signals to both ATM and ATR: Role of the mismatch repair system. Mol Pharmacol. 66:478–491. 2004.PubMed/NCBI

29 

Ruffini F, D’Atri S and Lacal PM: Neuropilin-1 expression promotes invasiveness of melanoma cells through vascular endothelial growth factor receptor-2-dependent and -independent mechanisms. Int J Oncol. 43:297–306. 2013.PubMed/NCBI

30 

Naber HP, Wiercinska E, Ten Dijke P and van Laar T: Spheroid assay to measure TGF-β-induced invasion. J Vis Exp. 57:e33372011.

31 

Merz C, Strecker A, Sykora J, Hill O, Fricke H, Angel P, Gieffers C and Peterziel H: Neutralization of the CD95 ligand by APG101 inhibits invasion of glioma cells in vitro. Anticancer Drugs. 26:716–727. 2015. View Article : Google Scholar : PubMed/NCBI

32 

Lacal PM, Failla CM, Pagani E, Odorisio T, Schietroma C, Falcinelli S, Zambruno G and D’Atri S: Human melanoma cells secrete and respond to placenta growth factor and vascular endothelial growth factor. J Invest Dermatol. 115:1000–1007. 2000. View Article : Google Scholar : PubMed/NCBI

33 

Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau HT, Brown MP, Hamid O, Infante JR, Millward M, Pavlick A, et al: Dose selection, pharmacokinetics, and pharmacodynamics of BRAF inhibitor dabrafenib (GSK2118436). Clin Cancer Res. 20:4449–4458. 2014. View Article : Google Scholar : PubMed/NCBI

34 

Smalley KS, Lioni M and Herlyn M: Life isn’t flat: Taking cancer biology to the next dimension. In Vitro Cell Dev Biol Anim. 42:242–247. 2006. View Article : Google Scholar : PubMed/NCBI

35 

Lacal PM, Ruffini F, Pagani E and D’Atri S: An autocrine loop directed by the vascular endothelial growth factor promotes invasiveness of human melanoma cells. Int J Oncol. 27:1625–1632. 2005.PubMed/NCBI

36 

Liu C, Peng W, Xu C, Lou Y, Zhang M, Wargo JA, Chen JQ, Li HS, Watowich SS, Yang Y, et al: BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. Clin Cancer Res. 19:393–403. 2013. View Article : Google Scholar

37 

Beazley-Long N, Gaston K, Harper SJ, Orlando A and Bates DO: Novel mechanisms of resistance to vemurafenib in melanoma - V600E B-Raf reversion and switching VEGF-A splice isoform expression. Am J Cancer Res. 5:433–441. 2014.

38 

Ferrara N, Hillan KJ, Gerber HP and Novotny W: Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 3:391–400. 2004. View Article : Google Scholar : PubMed/NCBI

39 

Keating GM: Bevacizumab: A review of its use in advanced cancer. Drugs. 74:1891–1925. 2014. View Article : Google Scholar : PubMed/NCBI

40 

Koch S, Tugues S, Li X, Gualandi L and Claesson-Welsh L: Signal transduction by vascular endothelial growth factor receptors. Biochem J. 437:169–183. 2011. View Article : Google Scholar : PubMed/NCBI

41 

Goel HL and Mercurio AM: VEGF targets the tumour cell. Nat Rev Cancer. 13:871–882. 2013. View Article : Google Scholar : PubMed/NCBI

42 

Graells J, Vinyals A, Figueras A, Llorens A, Moreno A, Marcoval J, Gonzalez FJ and Fabra A: Overproduction of VEGF concomitantly expressed with its receptors promotes growth and survival of melanoma cells through MAPK and PI3K signaling. J Invest Dermatol. 123:1151–1161. 2004. View Article : Google Scholar : PubMed/NCBI

43 

Greger JG, Eastman SD, Zhang V, Bleam MR, Hughes AM, Smitheman KN, Dickerson SH, Laquerre SG, Liu L and Gilmer TM: Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Mol Cancer Ther. 11:909–920. 2012. View Article : Google Scholar : PubMed/NCBI

44 

Kessenbrock K, Plaks V and Werb Z: Matrix metalloproteinases: Regulators of the tumor microenvironment. Cell. 141:52–67. 2010. View Article : Google Scholar : PubMed/NCBI

45 

Gialeli C, Theocharis AD and Karamanos NK: Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 278:16–27. 2011. View Article : Google Scholar

46 

Orgaz JL and Sanz-Moreno V: Emerging molecular targets in melanoma invasion and metastasis. Pigment Cell Melanoma Res. 26:39–57. 2013. View Article : Google Scholar

47 

Ghosh S, Basu M and Roy SS: ETS-1 protein regulates vascular endothelial growth factor-induced matrix metalloproteinase-9 and matrix metalloproteinase-13 expression in human ovarian carcinoma cell line SKOV-3. J Biol Chem. 287:15001–15015. 2012. View Article : Google Scholar : PubMed/NCBI

48 

Claesson-Welsh L and Welsh M: VEGFA and tumour angiogenesis. J Intern Med. 273:114–127. 2013. View Article : Google Scholar

49 

Carlino MS, Gowrishankar K, Saunders CAB, Pupo GM, Snoyman S, Zhang XD, Saw R, Becker TM, Kefford RF, Long GV, et al: Antiproliferative effects of continued mitogen-activated protein kinase pathway inhibition following acquired resistance to BRAF and/or MEK inhibition in melanoma. Mol Cancer Ther. 12:1332–1342. 2013. View Article : Google Scholar : PubMed/NCBI

50 

Chan MMK, Haydu LE, Menzies AM, Azer MWF, Klein O, Lyle M, Clements A, Guminski A, Kefford RF and Long GV: The nature and management of metastatic melanoma after progression on BRAF inhibitors: Effects of extended BRAF inhibition. Cancer. 120:3142–3153. 2014. View Article : Google Scholar : PubMed/NCBI

51 

Das Thakur M, Salangsang F, Landman AS, Sellers WR, Pryer NK, Levesque MP, Dummer R, McMahon M and Stuart DD: Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature. 494:251–255. 2013. View Article : Google Scholar : PubMed/NCBI

52 

Hartsough EJ, Basile KJ and Aplin AE: Beneficial effects of RAF inhibitor in mutant BRAF splice variant-expressing melanoma. Mol Cancer Res. 12:795–802. 2014. View Article : Google Scholar : PubMed/NCBI

53 

Mehnert JM, McCarthy MM, Jilaveanu L, Flaherty KT, Aziz S, Camp RL, Rimm DL and Kluger HM: Quantitative expression of VEGF, VEGF-R1, VEGF-R2, and VEGF-R3 in melanoma tissue microarrays. Hum Pathol. 41:375–384. 2010. View Article : Google Scholar

54 

Jiang CC, Lai F, Thorne RF, Yang F, Liu H, Hersey P and Zhang XD: MEK-independent survival of B-RAFV600E melanoma cells selected for resistance to apoptosis induced by the RAF inhibitor PLX4720. Clin Cancer Res. 17:721–730. 2011. View Article : Google Scholar

55 

Shi H, Kong X, Ribas A and Lo RS: Combinatorial treatments that overcome PDGFRβ-driven resistance of melanoma cells to V600EB-RAF inhibition. Cancer Res. 71:5067–5074. 2011. View Article : Google Scholar : PubMed/NCBI

56 

Atefi M, von Euw E, Attar N, Ng C, Chu C, Guo D, Nazarian R, Chmielowski B, Glaspy JA, Comin-Anduix B, et al: Reversing melanoma cross-resistance to BRAF and MEK inhibitors by co-targeting the AKT/mTOR pathway. PLoS One. 6:e289732011. View Article : Google Scholar : PubMed/NCBI

57 

Su F, Bradley WD, Wang Q, Yang H, Xu L, Higgins B, Kolinsky K, Packman K, Kim MJ, Trunzer K, et al: Resistance to selective BRAF inhibition can be mediated by modest upstream pathway activation. Cancer Res. 72:969–978. 2012. View Article : Google Scholar

58 

Lassen A, Atefi M, Robert L, Wong DJ, Cerniglia M, Comin-Anduix B and Ribas A: Effects of AKT inhibitor therapy in response and resistance to BRAF inhibition in melanoma. Mol Cancer. 13:832014. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Caporali S, Alvino E, Lacal PM, Levati L, Giurato G, Memoli D, Caprini E, Antonini Cappellini GC and D'Atri S: Targeting the PI3K/AKT/mTOR pathway overcomes the stimulating effect of dabrafenib on the invasive behavior of melanoma cells with acquired resistance to the BRAF inhibitor. Int J Oncol 49: 1164-1174, 2016.
APA
Caporali, S., Alvino, E., Lacal, P.M., Levati, L., Giurato, G., Memoli, D. ... D'Atri, S. (2016). Targeting the PI3K/AKT/mTOR pathway overcomes the stimulating effect of dabrafenib on the invasive behavior of melanoma cells with acquired resistance to the BRAF inhibitor. International Journal of Oncology, 49, 1164-1174. https://doi.org/10.3892/ijo.2016.3594
MLA
Caporali, S., Alvino, E., Lacal, P. M., Levati, L., Giurato, G., Memoli, D., Caprini, E., Antonini Cappellini, G. C., D'Atri, S."Targeting the PI3K/AKT/mTOR pathway overcomes the stimulating effect of dabrafenib on the invasive behavior of melanoma cells with acquired resistance to the BRAF inhibitor". International Journal of Oncology 49.3 (2016): 1164-1174.
Chicago
Caporali, S., Alvino, E., Lacal, P. M., Levati, L., Giurato, G., Memoli, D., Caprini, E., Antonini Cappellini, G. C., D'Atri, S."Targeting the PI3K/AKT/mTOR pathway overcomes the stimulating effect of dabrafenib on the invasive behavior of melanoma cells with acquired resistance to the BRAF inhibitor". International Journal of Oncology 49, no. 3 (2016): 1164-1174. https://doi.org/10.3892/ijo.2016.3594
Copy and paste a formatted citation
x
Spandidos Publications style
Caporali S, Alvino E, Lacal PM, Levati L, Giurato G, Memoli D, Caprini E, Antonini Cappellini GC and D'Atri S: Targeting the PI3K/AKT/mTOR pathway overcomes the stimulating effect of dabrafenib on the invasive behavior of melanoma cells with acquired resistance to the BRAF inhibitor. Int J Oncol 49: 1164-1174, 2016.
APA
Caporali, S., Alvino, E., Lacal, P.M., Levati, L., Giurato, G., Memoli, D. ... D'Atri, S. (2016). Targeting the PI3K/AKT/mTOR pathway overcomes the stimulating effect of dabrafenib on the invasive behavior of melanoma cells with acquired resistance to the BRAF inhibitor. International Journal of Oncology, 49, 1164-1174. https://doi.org/10.3892/ijo.2016.3594
MLA
Caporali, S., Alvino, E., Lacal, P. M., Levati, L., Giurato, G., Memoli, D., Caprini, E., Antonini Cappellini, G. C., D'Atri, S."Targeting the PI3K/AKT/mTOR pathway overcomes the stimulating effect of dabrafenib on the invasive behavior of melanoma cells with acquired resistance to the BRAF inhibitor". International Journal of Oncology 49.3 (2016): 1164-1174.
Chicago
Caporali, S., Alvino, E., Lacal, P. M., Levati, L., Giurato, G., Memoli, D., Caprini, E., Antonini Cappellini, G. C., D'Atri, S."Targeting the PI3K/AKT/mTOR pathway overcomes the stimulating effect of dabrafenib on the invasive behavior of melanoma cells with acquired resistance to the BRAF inhibitor". International Journal of Oncology 49, no. 3 (2016): 1164-1174. https://doi.org/10.3892/ijo.2016.3594
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