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Inactivation of Receptor Tyrosine Kinases Overcomes Resistance to Targeted B-RAF Inhibitors in Melanoma Cell Lines

  • Molecular Cell Biology
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Abstract

The discovery of B-RAF activating mutations in malignant melanoma cells has led to the development of a number of targeted drugs, which block exclusively the mutant B-RAF protein. Tumor cells often acquire resistance to B-RAF inhibitors via activation of alternative signaling pathways. One of the resistance mechanisms is activation of PDGF, VEGF, c-KIT, and certain other tyrosine kinases. The possibility of overcoming the resistance to the B-RAF inhibitor Vemurafenib by inactivating receptor tyrosine kinases (RTKs) was studied in metastatic melanoma cell lines differing in B-RAF mutations and RTK activity. It was found that RTK inactivation may help to overcome resistance to B-RAF inhibitors via inhibition of tyrosine kinase phosphorylation and a subsequent blocking of the PI3K-AKT-mTOR and MEK-ERK1/2 downstream signaling pathways. The changes eventually mitigated the cell growth and enhanced the Vemurafenibdependent cell cycle arrest.

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Abbreviations

DMSO:

dimethyl sulfoxide

MM:

metastatic melanoma

MTT:

3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide

RTK:

receptor tyrosine kinase

TGI:

tumor growth inhibition

FBS:

fetal bovine serum

EDTA:

ethylenediaminetetraacetic acid

AKT:

RAC-α-serine/threonineprotein kinase

B-RAF:

B-Raf proto-оncogene, serine/threonine kinase

CD31:

cluster of differentiation 31 (platelet endothelial cell adhesion molecule)

ErbB/HER:

epidermal growth factor receptor

ERK1/2:

extracellular signal-regulated kinase 1/2

c-KIT:

thyrosine protein kinase KIT (mast/stem cell growth factor receptor)

MEK:

mitogen-activated protein kinase kinase

c-MET:

tyrosine-protein kinase Met (hepatocyte growth factor)

PDGF:

platelet-derived growth factor

PDGFRα and PDGFRβ:

platelet-derived growth factor receptors α and β

PI3K:

phosphoinositide 3-kinase

mTOR:

mammalian target of rapamycin

VEGF:

vascular endothelial growth factor

VEGFR2:

vascular endothelial growth factor receptor 2

References

  1. Soura E., Eliades P.J., Shannon K., et al. 2016. Hereditary melanoma: Update on syndromes and management: Emerging melanoma cancer complexes and genetic counseling. J. Am. Acad. Dermatol. 74, 411–420.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Ndoye A., Weeraratna A.T. 2016. Autophagy: An emerging target for melanoma therapy. F1000Research. 5, 1888–1896.

    Article  CAS  Google Scholar 

  3. Wan P.T., Garnett M.J., Roe S.M., et al. 2004. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 116, 855–867.

    Article  PubMed  CAS  Google Scholar 

  4. Karasarides M., Chiloeches A., Hayward R., et al. 2004. B-RAF is a therapeutic target in melanoma. Oncogene. 23, 6292–6298.

    Article  PubMed  CAS  Google Scholar 

  5. Cohen C., Zavala-Pompa A., Sequeira J.H., et al. 2002. Mitogen-actived protein kinase activation is an early event in melanoma progression. Clin. Cancer Res. 8, 3728–3733.

    PubMed  CAS  Google Scholar 

  6. Lopez-Bergami P. 2011. The role of mitogen-and stress-activated protein kinase pathways in melanoma. Pigment Cell Melanoma Res. 24, 902–921.

    Article  PubMed  CAS  Google Scholar 

  7. Flaherty K.T., Puzanov I., Kim K.B., et al. 2010. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Lee W.R., Shen S.C., Shih Y.H., et al. 2015. Early decline in serum phospho-CSE1L levels in Vemurafenib/Sunitinib-treated melanoma and sorafenib/lapatinib-treated colorectal tumor xenografts. J. Transl. Med. 13, 191.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Emery C.M., Vijayendran K.G., Zipser M.C., et al. 2009. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc. Natl. Acad. Sci. U. S. A. 106, 20411–20416.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Nazarian R., Shi H., Wang Q., et al. 2010. Melanomas acquire resistance to B-RAF (V600E) inhibition by RTK or N-RAS upregulation. Nature. 468, 973–977.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Wagle N., Emery C., Berger M.F., et al. 2011. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J. Clin. Oncol. 29, 3085–3096.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Paraiso K.H., Xiang Y., Rebecca V.W., et al. 2011. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res. 71, 2750–2760.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Shi H., Kong X., Ribas A., Lo R.S. 2011. Combinatorial treatments that overcome PDGFRbeta-driven resistance of melanoma cells to V600EB-RAF inhibition. Cancer Res. 71, 5067–5074.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Sabbatino F., Wang Y., Wang X., et al. 2014. PDGFRα up-regulation mediated by Sonic Hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation. Oncotarget. 5, 1926–1941.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Graells J., Vinyals A., Figueras A., et al. 2004. 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.

    Article  PubMed  CAS  Google Scholar 

  16. Villanueva J., Vultur A., Lee J.T., et al. 2010. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell. 18, 683–695.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Pawson T. 2004. Specificity in signal transduction: from phosphotyrosine-SH2 domain interactions to complex cellular systems. Cell. 116, 191–203.

    Article  PubMed  CAS  Google Scholar 

  18. Fattore L., Marra E., Pisanu M.E., et al. 2013. Activation of an early feedback survival loop involving phosphor-ErbB3 is a general response of melanoma cells to RAF/MEK inhibition and is abrogated by anti-ErbB3 antibodies. J. Transl. Med. 11, 180–191.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Wandzioch E., Edling C.E., Palmer R.H., et al. 2004. Activation of the MAP kinase pathway by c-Kit is PI3 kinase dependent in hematopoietic progenitor/stem cell lines. Blood. 104, 51–57.

    Article  PubMed  CAS  Google Scholar 

  20. Halaban R., Zhang W., Bacchiocchi A., et al. 2010. PLX4032, a selective BRAFV600E kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAFWT melanoma cells. Pigm. Cell Melanoma Res. 23, 190–200.

    Article  CAS  Google Scholar 

  21. Heidorn S.J., Milagre C., Whittaker S., et al. 2010. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 140, 209–221.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Subbiah V., Meric-Bernstam F., Mills G.B., et al. 2014. Next generation sequencing analysis of platinum refractory advanced germ cell tumor sensitive to Sunitinib (Sutent®), a VEGFR2/PDGFRβ/c-kit/FLT3/RET/CSF1R inhibitor, in a phase II trial. J. Hematol. Oncol. 7, 52.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Mikhaylova I.N., Lukashina M.I., Barishnikov A. Yu., Morozova L.F., Burova O.S., Palkina T.N., Kozlov A.M., Golubeva V.A., Cheryomushkin Ye.A. 2005. Melanoma cell lines as the basis for antitumor vaccine preparation. Vestn. Ross. Akad. Med. Nauk. 7, 37–40.

    Google Scholar 

  24. Mikhaylova I.N., Kovalevsky D.A., Morozova L.F., et al. 2008. Cancer/testis genes expression in human melanoma cell lines. Melanoma Res. 5, 303–313.

    Article  CAS  Google Scholar 

  25. Andrae J., Gallini R., Betsholtz C. 2008. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 22, 1276–1312.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Radisavljevic Z. 2004. Locus of fragility in robust breast cancer system. J. Cell Biochem. 92, 1020–1024.

    Article  PubMed  CAS  Google Scholar 

  27. Yeramian A., Sorolla A., Velasco A., et al. 2012. Inhibition of activated receptor tyrosine kinases by Sunitinib induces growth arrest and sensitizes melanoma cells to Bortezomib by blocking Akt pathway. Int. J. Cancer. 130, 967–978.

    Article  PubMed  CAS  Google Scholar 

  28. Sun C., Wang L., Huang S., et al. 2014. Reversible and adaptive resistance to BRAF (V600E) inhibition in melanoma. Nature. 508, 118–122.

    Article  PubMed  CAS  Google Scholar 

  29. Straussman R., Morikawa T., Shee K., et al. 2012. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 487, 500–504.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Graells J., Vinyals A., Figueras A., et al. 2004. 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.

    Article  PubMed  CAS  Google Scholar 

  31. Kim K.B., Eton O., Davis D.W., et al. 2008. Phase II trial of imatinib mesylate in patients with metastatic melanoma. Br. J. Cancer. 99, 734–740.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Curtin J.A., Pinkel D., Bastian B.C. 2008. Absence of PDGFRA mutations in primary melanoma. J. Invest. Dermatol. 128, 488–489.

    Article  PubMed  CAS  Google Scholar 

  33. Shen S.S., Zhang P.S., Eton O., Prieto V.G. 2003. Analysis of protein tyrosine kinase expression in melanocytic lesions by tissue array. J. Cutaneous Pathol. 30, 539–547.

    Article  Google Scholar 

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Authors and Affiliations

  1. Blokhin Cancer Research Center, Ministry of Health of the Russian Federation, Moscow, 115478, Russia

    O. O. Ryabaya, A. A. Malysheva, Yu. A. Khochenkova, E. Sh. Solomko & D. A. Khochenkov

  2. Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, Moscow, 117997, Russia

    O. O. Ryabaya

Authors
  1. O. O. Ryabaya
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  2. A. A. Malysheva
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  3. Yu. A. Khochenkova
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  4. E. Sh. Solomko
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  5. D. A. Khochenkov
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Correspondence to O. O. Ryabaya.

Additional information

Original Russian Text © O.O. Ryabaya, A.A. Malysheva, Yu.A. Khochenkova, E.Sh. Solomko, D.A. Khochenkov, 2018, published in Molekulyarnaya Biologiya, 2018, Vol. 52, No. 3, pp. 466–473.

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Ryabaya, O.O., Malysheva, A.A., Khochenkova, Y.A. et al. Inactivation of Receptor Tyrosine Kinases Overcomes Resistance to Targeted B-RAF Inhibitors in Melanoma Cell Lines. Mol Biol 52, 398–405 (2018). https://doi.org/10.1134/S0026893318020115

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  • DOI: https://doi.org/10.1134/S0026893318020115

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