Cancer and Metastasis Reviews

, Volume 36, Issue 1, pp 23–33 | Cite as

Crosstalk signaling in targeted melanoma therapy

  • Svenja MeierjohannEmail author


Inhibition of the BRAF/MAPK pathway belongs to the standard therapies for patients with activating BRAFV600E/K mutations. However, even in well-responding tumors, anti-tumorigenic effect and clinical benefit are only transient, and the original tumors often relapse. This demonstrates that there are remaining residual tumors, which have withstood therapy-induced apoptosis and which have the potential to resume growth. Although BRAF mutant melanoma cells seem to depend on BRAF/MAPK signaling, the inhibition of this pathway triggers several events, which modulate the tumor as well as the tumor niche. After a certain adaptation period, this can turn out to be beneficial for tumor growth and metastasis—even in cases of good initial tumor response. This review sheds light on the biology of BRAF/MEK inhibitor-sensitive melanoma cells, which survive targeted therapy and will address the crosstalk signaling events occurring in BRAF mutant melanomas when the BRAF/MAPK pathway is fully blocked. The knowledge of these events is important for potential future drug combinations, which enhance the inhibitory effect of BRAF/MEK inhibition, particularly in patients not eligible for immune therapy.


Melanoma therapy MITF WNT EGFR Negative feedback Tumor microenvironment 



The author is supported by the Interdisciplinary Center for Clinical Research (University Hospital Würzburg, grant number B-323) and by the research unit FOR2314 (German Research Foundation).

I apologize to all authors whose work could not be referenced owing to space limitations.

Compliance with ethical standards

Conflict of interest

The author declares that she has no conflict of interest.


  1. 1.
    Chapman, P. B., Hauschild, A., Robert, C., Haanen, J. B., Ascierto, P., Larkin, J., et al. (2011). Improved survival with vemurafenib in melanoma with BRAF V600E mutation. The New England Journal of Medicine, 364(26), 2507–2516. doi: 10.1056/NEJMoa1103782.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Hauschild, A., Grob, J. J., Demidov, L. V., Jouary, T., Gutzmer, R., Millward, M., et al. (2012). Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet, 380(9839), 358–365. doi: 10.1016/S0140-6736(12)60868-X.CrossRefPubMedGoogle Scholar
  3. 3.
    Hodi, F. S., O’Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., et al. (2010). Improved survival with ipilimumab in patients with metastatic melanoma. The New England Journal of Medicine, 363(8), 711–723. doi: 10.1056/NEJMoa1003466.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Robert, C., Schachter, J., Long, G. V., Arance, A., Grob, J. J., Mortier, L., et al. (2015). Pembrolizumab versus Ipilimumab in advanced melanoma. The New England Journal of Medicine, 372(26), 2521–2532. doi: 10.1056/NEJMoa1503093.CrossRefPubMedGoogle Scholar
  5. 5.
    Weber, J. S., D’Angelo, S. P., Minor, D., Hodi, F. S., Gutzmer, R., Neyns, B., et al. (2015). Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. The Lancet Oncology, 16(4), 375–384. doi: 10.1016/S1470-2045(15)70076-8.CrossRefPubMedGoogle Scholar
  6. 6.
    Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J. J., Cowey, C. L., Lao, C. D., et al. (2015). Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. The New England Journal of Medicine, 373(1), 23–34. doi: 10.1056/NEJMoa1504030.CrossRefPubMedGoogle Scholar
  7. 7.
    Van Allen, E. M., Miao, D., Schilling, B., Shukla, S. A., Blank, C., Zimmer, L., et al. (2015). Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science, 350(6257), 207–211. doi: 10.1126/science.aad0095.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    McGranahan, N., Furness, A. J., Rosenthal, R., Ramskov, S., Lyngaa, R., Saini, S. K., et al. (2016). Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science, 351(6280), 1463–1469. doi: 10.1126/science.aaf1490.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Lee, J. T., Li, L., Brafford, P. A., van den Eijnden, M., Halloran, M. B., Sproesser, K., et al. (2010). PLX4032, a potent inhibitor of the B-Raf V600E oncogene, selectively inhibits V600E-positive melanomas. Pigment Cell & Melanoma Research, 23(6), 820–827. doi: 10.1111/j.1755-148X.2010.00763.x.CrossRefGoogle Scholar
  10. 10.
    Haferkamp, S., Borst, A., Adam, C., Becker, T. M., Motschenbacher, S., Windhovel, S., et al. (2013). Vemurafenib induces senescence features in melanoma cells. The Journal of Investigative Dermatology, 133(6), 1601–1609. doi: 10.1038/jid.2013.6.CrossRefPubMedGoogle Scholar
  11. 11.
    Gadiot, J., Hooijkaas, A. I., Deken, M. A., & Blank, C. U. (2013). Synchronous BRAF(V600E) and MEK inhibition leads to superior control of murine melanoma by limiting MEK inhibitor induced skin toxicity. Onco Targets Ther, 6, 1649–1658. doi: 10.2147/OTT.S52552.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Wagle, N., Emery, C., Berger, M. F., Davis, M. J., Sawyer, A., Pochanard, P., et al. (2011). Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. Journal of Clinical Oncology, 29(22), 3085–3096. doi: 10.1200/JCO.2010.33.2312.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Rizos, H., Menzies, A. M., Pupo, G. M., Carlino, M. S., Fung, C., Hyman, J., et al. (2014). BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clinical Cancer Research, 20(7), 1965–1977. doi: 10.1158/1078-0432.CCR-13-3122.CrossRefPubMedGoogle Scholar
  14. 14.
    Van Allen, E. M., Wagle, N., Sucker, A., Treacy, D. J., Johannessen, C. M., Goetz, E. M., et al. (2014). The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discovery, 4(1), 94–109. doi: 10.1158/2159-8290.CD-13-0617.CrossRefPubMedGoogle Scholar
  15. 15.
    Long, G. V., Stroyakovskiy, D., Gogas, H., Levchenko, E., de Braud, F., Larkin, J., et al. (2014). Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. The New England Journal of Medicine, 371(20), 1877–1888. doi: 10.1056/NEJMoa1406037.CrossRefPubMedGoogle Scholar
  16. 16.
    Robert, C., Karaszewska, B., Schachter, J., Rutkowski, P., Mackiewicz, A., Stroiakovski, D., et al. (2015). Improved overall survival in melanoma with combined dabrafenib and trametinib. The New England Journal of Medicine, 372(1), 30–39. doi: 10.1056/NEJMoa1412690.CrossRefPubMedGoogle Scholar
  17. 17.
    Cheng, Y., Zhang, G., & Li, G. (2013). Targeting MAPK pathway in melanoma therapy. Cancer Metastasis Reviews, 32(3–4), 567–584. doi: 10.1007/s10555-013-9433-9.CrossRefPubMedGoogle Scholar
  18. 18.
    Murphy, T., Hori, S., Sewell, J., & Gnanapragasam, V. J. (2010). Expression and functional role of negative signalling regulators in tumour development and progression. International Journal of Cancer, 127(11), 2491–2499. doi: 10.1002/ijc.25542.CrossRefPubMedGoogle Scholar
  19. 19.
    Easty, D. J., Gray, S. G., O’Byrne, K. J., O’Donnell, D., & Bennett, D. C. (2011). Receptor tyrosine kinases and their activation in melanoma. Pigment Cell & Melanoma Research, 24(3), 446–461. doi: 10.1111/j.1755-148X.2011.00836.x.CrossRefGoogle Scholar
  20. 20.
    Lito, P., Pratilas, C. A., Joseph, E. W., Tadi, M., Halilovic, E., Zubrowski, M., et al. (2012). Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell, 22(5), 668–682. doi: 10.1016/j.ccr.2012.10.009.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Haydn, J. M., Hufnagel, A., Grimm, J., Maurus, K., Schartl, M., & Meierjohann, S. (2014). The MAPK pathway as an apoptosis enhancer in melanoma. Oncotarget, 5(13), 5040–5053. doi: 10.18632/oncotarget.2079.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Paraiso, K. H., Xiang, Y., Rebecca, V. W., Abel, E. V., Chen, Y. A., Munko, A. C., et al. (2011). PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Research, 71(7), 2750–2760. doi: 10.1158/0008-5472.CAN-10-2954.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Werzowa, J., Koehrer, S., Strommer, S., Cejka, D., Fuereder, T., Zebedin, E., et al. (2011). Vertical inhibition of the mTORC1/mTORC2/PI3K pathway shows synergistic effects against melanoma in vitro and in vivo. The Journal of Investigative Dermatology, 131(2), 495–503. doi: 10.1038/jid.2010.327.CrossRefPubMedGoogle Scholar
  24. 24.
    Sinnberg, T., Lasithiotakis, K., Niessner, H., Schittek, B., Flaherty, K. T., Kulms, D., et al. (2009). Inhibition of PI3K-AKT-mTOR signaling sensitizes melanoma cells to cisplatin and temozolomide. The Journal of Investigative Dermatology, 129(6), 1500–1515. doi: 10.1038/jid.2008.379.CrossRefPubMedGoogle Scholar
  25. 25.
    Gopal, Y. N., Deng, W., Woodman, S. E., Komurov, K., Ram, P., Smith, P. D., et al. (2010). Basal and treatment-induced activation of AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in Braf-mutant human cutaneous melanoma cells. Cancer Research, 70(21), 8736–8747. doi: 10.1158/0008-5472.CAN-10-0902.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Sun, C., Wang, L., Huang, S., Heynen, G. J., Prahallad, A., Robert, C., et al. (2014). Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature, 508(7494), 118–122. doi: 10.1038/nature13121.CrossRefPubMedGoogle Scholar
  27. 27.
    Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., et al. (2002). Mutations of the BRAF gene in human cancer. Nature, 417(6892), 949–954. doi: 10.1038/nature00766.CrossRefPubMedGoogle Scholar
  28. 28.
    Prahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., et al. (2012). Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature, 483(7387), 100–103. doi: 10.1038/nature10868.CrossRefPubMedGoogle Scholar
  29. 29.
    Corcoran, R. B., Ebi, H., Turke, A. B., Coffee, E. M., Nishino, M., Cogdill, A. P., et al. (2012). EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discovery, 2(3), 227–235. doi: 10.1158/2159-8290.CD-11-0341.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Abel, E. V., Basile, K. J., Kugel 3rd, C. H., Witkiewicz, A. K., Le, K., Amaravadi, R. K., et al. (2013). Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3. The Journal of Clinical Investigation, 123(5), 2155–2168. doi: 10.1172/JCI65780.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Fattore, L., Marra, E., Pisanu, M. E., Noto, A., de Vitis, C., Belleudi, F., et al. (2013). Activation of an early feedback survival loop involving phospho-ErbB3 is a general response of melanoma cells to RAF/MEK inhibition and is abrogated by anti-ErbB3 antibodies. Journal of Translational Medicine, 11, 180. doi: 10.1186/1479-5876-11-180.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kim, H. H., Sierke, S. L., & Koland, J. G. (1994). Epidermal growth factor-dependent association of phosphatidylinositol 3-kinase with the erbB3 gene product. The Journal of Biological Chemistry, 269(40), 24747–24755.PubMedGoogle Scholar
  33. 33.
    Abel, E. V., & Aplin, A. E. (2010). FOXD3 is a mutant B-RAF-regulated inhibitor of G(1)-S progression in melanoma cells. Cancer Research, 70(7), 2891–2900. doi: 10.1158/0008-5472.CAN-09-3139.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Capparelli, C., Rosenbaum, S., Berger, A. C., & Aplin, A. E. (2015). Fibroblast-derived neuregulin 1 promotes compensatory ErbB3 receptor signaling in mutant BRAF melanoma. The Journal of Biological Chemistry, 290(40), 24267–24277. doi: 10.1074/jbc.M115.657270.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Tiwary, S., Preziosi, M., Rothberg, P. G., Zeitouni, N., Corson, N., & Xu, L. (2014). ERBB3 is required for metastasis formation of melanoma cells. Oncogenesis, 3, e110. doi: 10.1038/oncsis.2014.23.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Nazarian, R., Shi, H., Wang, Q., Kong, X., Koya, R. C., Lee, H., et al. (2010). Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature, 468(7326), 973–977. doi: 10.1038/nature09626.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Sabbatino, F., Wang, Y., Wang, X., Flaherty, K. T., Yu, L., Pepin, D., et al. (2014). PDGFRalpha up-regulation mediated by sonic hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation. Oncotarget, 5(7), 1926–1941. doi: 10.18632/oncotarget.1878.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Stecca, B., Mas, C., Clement, V., Zbinden, M., Correa, R., Piguet, V., et al. (2007). Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proceedings of the National Academy of Sciences of the United States of America, 104(14), 5895–5900. doi: 10.1073/pnas.0700776104.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Villanueva, J., Vultur, A., Lee, J. T., Somasundaram, R., Fukunaga-Kalabis, M., Cipolla, A. K., 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(6), 683–695. doi: 10.1016/j.ccr.2010.11.023.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Vultur, A., Villanueva, J., Krepler, C., Rajan, G., Chen, Q., Xiao, M., et al. (2014). MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines. Oncogene, 33(14), 1850–1861. doi: 10.1038/onc.2013.131.CrossRefPubMedGoogle Scholar
  41. 41.
    Wellbrock, C., & Arozarena, I. (2015). Microphthalmia-associated transcription factor in melanoma development and MAP-kinase pathway targeted therapy. Pigment Cell & Melanoma Research, 28(4), 390–406. doi: 10.1111/pcmr.12370.CrossRefGoogle Scholar
  42. 42.
    Wellbrock, C., & Marais, R. (2005). Elevated expression of MITF counteracts B-RAF-stimulated melanocyte and melanoma cell proliferation. The Journal of Cell Biology, 170(5), 703–708. doi: 10.1083/jcb.200505059.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Wellbrock, C., Rana, S., Paterson, H., Pickersgill, H., Brummelkamp, T., & Marais, R. (2008). Oncogenic BRAF regulates melanoma proliferation through the lineage specific factor MITF. PloS One, 3(7), e2734. doi: 10.1371/journal.pone.0002734.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Rodriguez, C. I., & Setaluri, V. (2014). Cyclic AMP (cAMP) signaling in melanocytes and melanoma. Archives of Biochemistry and Biophysics, 563, 22–27. doi: 10.1016/ Scholar
  45. 45.
    Huber, W. E., Price, E. R., Widlund, H. R., Du, J., Davis, I. J., Wegner, M., et al. (2003). A tissue-restricted cAMP transcriptional response: SOX10 modulates alpha-melanocyte-stimulating hormone-triggered expression of microphthalmia-associated transcription factor in melanocytes. The Journal of Biological Chemistry, 278(46), 45224–45230. doi: 10.1074/jbc.M309036200.CrossRefPubMedGoogle Scholar
  46. 46.
    Johannessen, C. M., Johnson, L. A., Piccioni, F., Townes, A., Frederick, D. T., Donahue, M. K., et al. (2013). A melanocyte lineage program confers resistance to MAP kinase pathway inhibition. Nature, 504(7478), 138–142. doi: 10.1038/nature12688.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Gopal, Y. N., Rizos, H., Chen, G., Deng, W., Frederick, D. T., Cooper, Z. A., et al. (2014). Inhibition of mTORC1/2 overcomes resistance to MAPK pathway inhibitors mediated by PGC1alpha and oxidative phosphorylation in melanoma. Cancer Research, 74(23), 7037–7047. doi: 10.1158/0008-5472.CAN-14-1392.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Haq, R., Shoag, J., Andreu-Perez, P., Yokoyama, S., Edelman, H., Rowe, G. C., et al. (2013). Oncogenic BRAF regulates oxidative metabolism via PGC1alpha and MITF. Cancer Cell, 23(3), 302–315. doi: 10.1016/j.ccr.2013.02.003.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Smith, M. P., Brunton, H., Rowling, E. J., Ferguson, J., Arozarena, I., Miskolczi, Z., et al. (2016). Inhibiting drivers of non-mutational drug tolerance is a salvage strategy for targeted melanoma therapy. Cancer Cell, 29(3), 270–284. doi: 10.1016/j.ccell.2016.02.003.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Konieczkowski, D. J., Johannessen, C. M., Abudayyeh, O., Kim, J. W., Cooper, Z. A., Piris, A., et al. (2014). A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors. Cancer Discovery, 4(7), 816–827. doi: 10.1158/2159-8290.CD-13-0424.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Muller, J., Krijgsman, O., Tsoi, J., Robert, L., Hugo, W., Song, C., et al. (2014). Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Nature Communications, 5, 5712. doi: 10.1038/ncomms6712.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Sensi, M., Catani, M., Castellano, G., Nicolini, G., Alciato, F., Tragni, G., et al. (2011). Human cutaneous melanomas lacking MITF and melanocyte differentiation antigens express a functional Axl receptor kinase. The Journal of Investigative Dermatology, 131(12), 2448–2457. doi: 10.1038/jid.2011.218.CrossRefPubMedGoogle Scholar
  53. 53.
    Tirosh, I., Izar, B., Prakadan, S. M., Wadsworth 2nd, M. H., Treacy, D., Trombetta, J. J., et al. (2016). Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science, 352(6282), 189–196. doi: 10.1126/science.aad0501.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Alver, T. N., Lavelle, T. J., Longva, A. S., Oy, G. F., Hovig, E., & Boe, S. L. (2016). MITF depletion elevates expression levels of ERBB3 receptor and its cognate ligand NRG1-beta in melanoma. Oncotarget. doi: 10.18632/oncotarget.10422.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Ueno, Y., Sakurai, H., Tsunoda, S., Choo, M. K., Matsuo, M., Koizumi, K., et al. (2008). Heregulin-induced activation of ErbB3 by EGFR tyrosine kinase activity promotes tumor growth and metastasis in melanoma cells. International Journal of Cancer, 123(2), 340–347. doi: 10.1002/ijc.23465.CrossRefPubMedGoogle Scholar
  56. 56.
    Boone, B., Jacobs, K., Ferdinande, L., Taildeman, J., Lambert, J., Peeters, M., et al. (2011). EGFR in melanoma: clinical significance and potential therapeutic target. Journal of Cutaneous Pathology, 38(6), 492–502. doi: 10.1111/j.1600-0560.2011.01673.x.CrossRefPubMedGoogle Scholar
  57. 57.
    Buac, K., Xu, M., Cronin, J., Weeraratna, A. T., Hewitt, S. M., & Pavan, W. J. (2009). NRG1 / ERBB3 signaling in melanocyte development and melanoma: inhibition of differentiation and promotion of proliferation. Pigment Cell & Melanoma Research, 22(6), 773–784. doi: 10.1111/j.1755-148X.2009.00616.x.CrossRefGoogle Scholar
  58. 58.
    Kundu, A., Quirit, J. G., Khouri, M. G., & Firestone, G. L. (2016). Inhibition of oncogenic BRAF activity by indole-3-carbinol disrupts microphthalmia-associated transcription factor expression and arrests melanoma cell proliferation. Molecular Carcinogenesis. doi: 10.1002/mc.22472.PubMedCentralGoogle Scholar
  59. 59.
    Xue, G., Romano, E., Massi, D., & Mandala, M. (2016). Wnt/beta-catenin signaling in melanoma: preclinical rationale and novel therapeutic insights. Cancer Treatment Reviews, 49, 1–12. doi: 10.1016/j.ctrv.2016.06.009.CrossRefPubMedGoogle Scholar
  60. 60.
    Larue, L., & Beermann, F. (2007). Cutaneous melanoma in genetically modified animals. Pigment Cell Research, 20(6), 485–497. doi: 10.1111/j.1600-0749.2007.00411.x.CrossRefPubMedGoogle Scholar
  61. 61.
    Biechele, T. L., Kulikauskas, R. M., Toroni, R. A., Lucero, O. M., Swift, R. D., James, R. G., et al. (2012). Wnt/beta-catenin signaling and AXIN1 regulate apoptosis triggered by inhibition of the mutant kinase BRAFV600E in human melanoma. Science Signaling, 5(206), ra3. doi: 10.1126/scisignal.2002274.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Kaur, A., Webster, M. R., Marchbank, K., Behera, R., Ndoye, A., Kugel 3rd, C. H., et al. (2016). sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature, 532(7598), 250–254. doi: 10.1038/nature17392.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    O’Connell, M. P., Marchbank, K., Webster, M. R., Valiga, A. A., Kaur, A., Vultur, A., et al. (2013). Hypoxia induces phenotypic plasticity and therapy resistance in melanoma via the tyrosine kinase receptors ROR1 and ROR2. Cancer Discovery, 3(12), 1378–1393. doi: 10.1158/2159-8290.CD-13-0005.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Anastas, J. N., Kulikauskas, R. M., Tamir, T., Rizos, H., Long, G. V., von Euw, E. M., et al. (2014). WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors. The Journal of Clinical Investigation, 124(7), 2877–2890. doi: 10.1172/JCI70156.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Dissanayake, S. K., Olkhanud, P. B., O’Connell, M. P., Carter, A., French, A. D., Camilli, T. C., et al. (2008). Wnt5A regulates expression of tumor-associated antigens in melanoma via changes in signal transducers and activators of transcription 3 phosphorylation. Cancer Research, 68(24), 10205–10214. doi: 10.1158/0008-5472.CAN-08-2149.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Straussman, R., Morikawa, T., Shee, K., Barzily-Rokni, M., Qian, Z. R., Du, J., et al. (2012). Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature, 487(7408), 500–504. doi: 10.1038/nature11183.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Li, Z., Jiang, K., Zhu, X., Lin, G., Song, F., Zhao, Y., et al. (2016). Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells. Cancer Letters, 370(2), 332–344. doi: 10.1016/j.canlet.2015.11.015.CrossRefPubMedGoogle Scholar
  68. 68.
    Ohanna, M., Giuliano, S., Bonet, C., Imbert, V., Hofman, V., Zangari, J., et al. (2011). Senescent cells develop a PARP-1 and nuclear factor-{kappa}B-associated secretome (PNAS). Genes & Development, 25(12), 1245–1261. doi: 10.1101/gad.625811.CrossRefGoogle Scholar
  69. 69.
    Hanna, S. C., Krishnan, B., Bailey, S. T., Moschos, S. J., Kuan, P. F., Shimamura, T., et al. (2013). HIF1alpha and HIF2alpha independently activate SRC to promote melanoma metastases. The Journal of Clinical Investigation, 123(5), 2078–2093. doi: 10.1172/JCI66715.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Shaverdashvili, K., Wong, P., Ma, J., Zhang, K., Osman, I., & Bedogni, B. (2014). MT1-MMP modulates melanoma cell dissemination and metastasis through activation of MMP2 and RAC1. Pigment Cell & Melanoma Research, 27(2), 287–296. doi: 10.1111/pcmr.12201.CrossRefGoogle Scholar
  71. 71.
    Ferguson, J., Arozarena, I., Ehrhardt, M., & Wellbrock, C. (2013). Combination of MEK and SRC inhibition suppresses melanoma cell growth and invasion. Oncogene, 32(1), 86–96. doi: 10.1038/onc.2012.25.CrossRefPubMedGoogle Scholar
  72. 72.
    Obenauf, A. C., Zou, Y., Ji, A. L., Vanharanta, S., Shu, W., Shi, H., et al. (2015). Therapy-induced tumour secretomes promote resistance and tumour progression. Nature, 520(7547), 368–372. doi: 10.1038/nature14336.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Fedorenko, I. V., Wargo, J. A., Flaherty, K. T., Messina, J. L., & Smalley, K. S. (2015). BRAF inhibition generates a host-tumor niche that mediates therapeutic escape. The Journal of Investigative Dermatology, 135(12), 3115–3124. doi: 10.1038/jid.2015.329.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Fedorenko, I. V., Abel, E. V., Koomen, J. M., Fang, B., Wood, E. R., Chen, Y. A., et al. (2016). Fibronectin induction abrogates the BRAF inhibitor response of BRAF V600E/PTEN-null melanoma cells. Oncogene, 35(10), 1225–1235. doi: 10.1038/onc.2015.188.CrossRefPubMedGoogle Scholar
  75. 75.
    Hirata, E., Girotti, M. R., Viros, A., Hooper, S., Spencer-Dene, B., Matsuda, M., et al. (2015). Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin beta1/FAK signaling. Cancer Cell, 27(4), 574–588. doi: 10.1016/j.ccell.2015.03.008.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Wang, T., Xiao, M., Ge, Y., Krepler, C., Belser, E., Lopez-Coral, A., et al. (2015). BRAF inhibition stimulates melanoma-associated macrophages to drive tumor growth. Clinical Cancer Research, 21(7), 1652–1664. doi: 10.1158/1078-0432.CCR-14-1554.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Ngiow, S. F., Meeth, K. M., Stannard, K., Barkauskas, D. S., Bollag, G., Bosenberg, M., et al. (2016). Co-inhibition of colony stimulating factor-1 receptor and BRAF oncogene in mouse models of BRAFV600E melanoma. Oncoimmunology, 5(3), e1089381. doi: 10.1080/2162402X.2015.1089381.CrossRefPubMedGoogle Scholar
  78. 78.
    Mok, S., Tsoi, J., Koya, R. C., Hu-Lieskovan, S., West, B. L., Bollag, G., et al. (2015). Inhibition of colony stimulating factor-1 receptor improves antitumor efficacy of BRAF inhibition. BMC Cancer, 15, 356. doi: 10.1186/s12885-015-1377-8.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Peske, J. D., Woods, A. B., & Engelhard, V. H. (2015). Control of CD8 T-cell infiltration into tumors by vasculature and microenvironment. Advances in Cancer Research, 128, 263–307. doi: 10.1016/bs.acr.2015.05.001.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Cooper, Z. A., Juneja, V. R., Sage, P. T., Frederick, D. T., Piris, A., Mitra, D., et al. (2014). Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade. Cancer Immunology Research, 2(7), 643–654. doi: 10.1158/2326-6066.CIR-13-0215.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Liu, C., Peng, W., Xu, C., Lou, Y., Zhang, M., Wargo, J. A., et al. (2013). BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. Clinical Cancer Research, 19(2), 393–403. doi: 10.1158/1078-0432.CCR-12-1626.CrossRefPubMedGoogle Scholar
  82. 82.
    Steinberg, S. M., Zhang, P., Malik, B. T., Boni, A., Shabaneh, T. B., Byrne, K. T., et al. (2014). BRAF inhibition alleviates immune suppression in murine autochthonous melanoma. Cancer Immunology Research, 2(11), 1044–1050. doi: 10.1158/2326-6066.CIR-14-0074.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Sapkota, B., Hill, C. E., & Pollack, B. P. (2013). Vemurafenib enhances MHC induction in BRAFV600E homozygous melanoma cells. Oncoimmunology, 2(1), e22890. doi: 10.4161/onci.22890.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Minor, D. R., Puzanov, I., Callahan, M. K., Hug, B. A., & Hoos, A. (2015). Severe gastrointestinal toxicity with administration of trametinib in combination with dabrafenib and ipilimumab. Pigment Cell & Melanoma Research, 28(5), 611–612. doi: 10.1111/pcmr.12383.CrossRefGoogle Scholar
  85. 85.
    Ribas, A., Hodi, F. S., Callahan, M., Konto, C., & Wolchok, J. (2013). Hepatotoxicity with combination of vemurafenib and ipilimumab. The New England Journal of Medicine, 368(14), 1365–1366. doi: 10.1056/NEJMc1302338.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department of Physiological Chemistry, BiocenterUniversity of WürzburgWürzburgGermany
  2. 2.Comprehensive Cancer Center MainfrankenUniversity Hospital WürzburgWürzburgGermany

Personalised recommendations