[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Tumor heterogeneity and plasticity as elusive drivers for resistance to MAPK pathway inhibition in melanoma

Oncogene volume 34, pages 2951–2957 (2015)Cite this article

Subjects

Abstract

Despite the recent success of MAPK signaling-targeted drugs in melanoma, the majority of patients with metastatic melanoma still undergo disease progression after initial tumor shrinkage indicating gradually developing therapy resistance. This review will give an overview on currently suggested concepts of resistance to MAPK pathway inhibitors in melanoma with particular focus on inter- and intraindividual as well as intratumor heterogeneity. The high plasticity of melanoma cells promotes both the clonal evolution of genetic resistance, for example, because of mutations in the MAPK or PI3K/AKT/PTEN pathways, and the emergence of cell phenotypes that functionally and metabolically overcome MAPK inhibition. Like a ‘moving target’, melanoma cells are shifting between different metabolic, cell cycle and differentiation states reflecting a highly dynamic potential to adapt to exogenous stressors including drugs. The introduction of MAPK inhibitors into the clinics has tremendously pushed the field of melanoma research not just because of the historic therapeutic success but also by providing a new tool to study human melanoma in its natural microenvironment.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009; 27: 6199–6206.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Schadendorf D, Hauschild A . Melanoma in 2013: Melanoma–the run of success continues. Nat Rev Clin Oncol 2014; 11: 75–76.

    Article  CAS  PubMed  Google Scholar 

  3. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New Engl J Med 2011; 364: 2507–2516.

    Article  CAS  PubMed  Google Scholar 

  4. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012; 380: 358–365.

    Article  CAS  PubMed  Google Scholar 

  5. McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 2014; 15: 323–332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. New Engl J Med 2012; 367: 107–114.

    Article  CAS  PubMed  Google Scholar 

  7. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. New Engl J Med 2012; 367: 1694–1703.

    Article  CAS  PubMed  Google Scholar 

  8. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA et al. Inhibition of mutated, activated BRAF in metastatic melanoma. New Engl J Med 2010; 363: 809–819.

    Article  CAS  PubMed  Google Scholar 

  9. Hartsough E, Shao Y, Aplin AE . Resistance to RAF Inhibitors Revisited. J Invest Dermatol 2014; 134: 319–325.

    Article  CAS  PubMed  Google Scholar 

  10. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. New Engl J Med 2012; 366: 707–714.

    Article  CAS  PubMed  Google Scholar 

  11. Lito P, Rosen N, Solit DB . Tumor adaptation and resistance to RAF inhibitors. Nat Med 2013; 19: 1401–1409.

    Article  CAS  PubMed  Google Scholar 

  12. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 2010; 468: 973–977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rizos H, Menzies AM, Pupo GM, Carlino MS, Fung C, Hyman J et al. BRAF Inhibitor Resistance Mechanisms in Metastatic Melanoma: Spectrum and Clinical Impact. Clin Cancer Res 2014; 20: 1965–1977.

    Article  CAS  PubMed  Google Scholar 

  14. Shi H, Hugo W, Kong X, Hong A, Koya RC, Moriceau G et al. Acquired resistance and clonal evolution in mMelanoma during BRAF inhibitor therapy. Cancer Discov 2013.

  15. Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM, Goetz EM et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov 2014; 4: 94–109.

    Article  CAS  PubMed  Google Scholar 

  16. Trunzer K, Pavlick AC, Schuchter L, Gonzalez R, McArthur GA, Hutson TE et al. Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. J Clin Oncol 2013; 31: 1767–1774.

    Article  CAS  PubMed  Google Scholar 

  17. Su F, Bradley WD, Wang Q, Yang H, Xu L, Higgins B et al. Resistance to selective BRAF inhibition can be mediated by modest upstream pathway activation. Cancer Res 2012; 72: 969–978.

    Article  CAS  PubMed  Google Scholar 

  18. Shi H, Moriceau G, Kong X, Lee MK, Lee H, Koya RC et al. Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun 2012; 3: 724.

    Article  PubMed  Google Scholar 

  19. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 2011; 480: 387–390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wagle N, Emery C, Berger MF, Davis MJ, Sawyer A, Pochanard P et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol 2011; 29: 3085–3096.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shi H, Moriceau G, Kong X, Koya RC, Nazarian R, Pupo GM et al. Preexisting MEK1 exon 3 mutations in V600E/KBRAF melanomas do not confer resistance to BRAF inhibitors. Cancer Discov 2012; 2: 414–424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nathanson KL, Martin AM, Wubbenhorst B, Greshock J, Letrero R, D'Andrea K et al. Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor dabrafenib (GSK2118436). Clin Cancer Res 2013; 19: 4868–4878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Villanueva J, Infante JR, Krepler C, Reyes-Uribe P, Samanta M, Chen HY et al. Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. Cell Rep 2013; 4: 1090–1099.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wagle N, Van Allen EM, Treacy DJ, Frederick DT, Cooper ZA, Taylor-Weiner A et al. MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer Discov 2014; 4: 61–68.

    Article  CAS  PubMed  Google Scholar 

  25. Johannessen CM, Johnson LA, Piccioni F, Townes A, Frederick DT, Donahue MK et al. A melanocyte lineage program confers resistance to MAP kinase pathway inhibition. Nature 2013; 504: 138–142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Romano E, Pradervand S, Paillusson A, Weber J, Harshman K, Muehlethaler K et al. Identification of multiple mechanisms of resistance to vemurafenib in a patient with BRAFV600E-mutated cutaneous melanoma successfully rechallenged after progression. Clin Cancer Res 2013; 19: 5749–5757.

    Article  CAS  PubMed  Google Scholar 

  27. Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 2010; 468: 968–972.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Montagut C, Sharma SV, Shioda T, McDermott U, Ulman M, Ulkus LE et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res 2008; 68: 4853–4861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Shao Y, Aplin AE . BH3-only protein silencing contributes to acquired resistance to PLX4720 in human melanoma. Cell Death Differ 2012; 19: 2029–2039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sun C, Wang L, Huang S, Heynen GJ, Prahallad A, Robert C et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 2014; 508: 118–122.

    Article  CAS  PubMed  Google Scholar 

  31. Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1 R/PI3K. Cancer Cell 2010; 18: 683–695.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov 2012; 2: 227–235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 2012; 483: 100–103.

    Article  CAS  PubMed  Google Scholar 

  34. Abel EV, Basile KJ, Kugel CH 3rd, Witkiewicz AK, Le K, Amaravadi RK et al. Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3. J Clin Invest 2013; 123: 2155–2168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Haq R, Shoag J, Andreu-Perez P, Yokoyama S, Edelman H, Rowe GC et al. Oncogenic BRAF regulates oxidative metabolism via PGC1alpha and MITF. Cancer Cell 2013; 23: 302–315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Corazao-Rozas P, Guerreschi P, Jendoubi M, Andre F, Jonneaux A, Scalbert C et al. Mitochondrial oxidative stress is the Achille's heel of melanoma cells resistant to Braf-mutant inhibitor. Oncotarget 2013; 4: 1986–1998.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Girnun GD . The diverse role of the PPARgamma coactivator 1 family of transcriptional coactivators in cancer. Semin Cell Dev Biol 2012; 23: 381–388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lin J, Handschin C, Spiegelman BM . Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 2005; 1: 361–370.

    PubMed  Google Scholar 

  40. Garraway LA, Widlund HR, Rubin MA, Getz G, Berger AJ, Ramaswamy S et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 2005; 436: 117–122.

    Article  CAS  PubMed  Google Scholar 

  41. Cheli Y, Giuliano S, Botton T, Rocchi S, Hofman V, Hofman P et al. Mitf is the key molecular switch between mouse or human melanoma initiating cells and their differentiated progeny. Oncogene 2011; 30: 2307–2318.

    Article  CAS  PubMed  Google Scholar 

  42. Hoek KS, Eichhoff OM, Schlegel NC, Dobbeling U, Kobert N, Schaerer L et al. In vivo switching of human melanoma cells between proliferative and invasive states. Cancer Res 2008; 68: 650–656.

    Article  CAS  PubMed  Google Scholar 

  43. Hoek KS, Goding CR . Cancer stem cells versus phenotype-switching in melanoma. Pigment Cell Melanoma Res 2010; 23: 746–759.

    Article  CAS  PubMed  Google Scholar 

  44. Widmer DS, Cheng PF, Eichhoff OM, Belloni BC, Zipser MC, Schlegel NC et al. Systematic classification of melanoma cells by phenotype-specific gene expression mapping. Pigment Cell Melanoma Res 2012; 25: 343–353.

    Article  CAS  PubMed  Google Scholar 

  45. Carreira S, Goodall J, Denat L, Rodriguez M, Nuciforo P, Hoek KS et al. Mitf regulation of Dia1 controls melanoma proliferation and invasiveness. Genes Dev 2006; 20: 3426–3439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Saez-Ayala M, Montenegro MF, Sanchez-Del-Campo L, Fernandez-Perez MP, Chazarra S, Freter R et al. Directed phenotype switching as an effective antimelanoma strategy. Cancer Cell 2013; 24: 105–119.

    Article  CAS  PubMed  Google Scholar 

  47. Jose C, Bellance N, Rossignol R . Choosing between glycolysis and oxidative phosphorylation: a tumor's dilemma? Biochim Biophys Acta 2011; 1807: 552–561.

    Article  CAS  PubMed  Google Scholar 

  48. Levine AJ, Puzio-Kuter AM . The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 2010; 330: 1340–1344.

    Article  CAS  PubMed  Google Scholar 

  49. Vander Heiden MG, Cantley LC, Thompson CB . Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324: 1029–1033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Berridge MV, Herst PM, Tan AS . Metabolic flexibility and cell hierarchy in metastatic cancer. Mitochondrion 2010; 10: 584–588.

    Article  CAS  PubMed  Google Scholar 

  51. Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 2010; 141: 69–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Roesch A, Fukunaga M, Schmidt E, Zabierowski S, Brafford P, Vultur A et al. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 2010; 141: 583–594.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Roesch A, Vultur A, Wang H, Speicher D, Bogeski I, Hoth M et al. Overcoming Intrinsic Multidrug Resistance in Melanoma by Blocking the Mitochondrial Respiratory Chain of Slow-Cycling JARID1B high Cells. Cancer Cell 2013; 23: 811–825.

    Article  CAS  PubMed  Google Scholar 

  54. Yuan P, Ito K, Perez-Lorenzo R, Del Guzzo C, Lee JH, Shen CH et al. Phenformin enhances the therapeutic benefit of BRAFV600E inhibition in melanoma. Proc Natl Acad Sci USA 2013; 110: 18226–18231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Haferkamp S, Borst A, Adam C, Becker TM, Motschenbacher S, Windhovel S et al. Vemurafenib induces senescence features in melanoma cells. J Invest Dermatol 2013; 133: 1601–1609.

    Article  CAS  PubMed  Google Scholar 

  56. Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 2012; 487: 500–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 2012; 487: 505–509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. O'Connell MP, Marchbank K, Webster MR, Valiga AA, Kaur A, Vultur A et al. Hypoxia induces phenotypic plasticity and therapy resistance in melanoma via the tyrosine kinase receptors ROR1 and ROR2. Cancer Discov 2013; 3: 1378–1393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Cheli Y, Giuliano S, Fenouille N, Allegra M, Hofman V, Hofman P et al. Hypoxia and MITF control metastatic behaviour in mouse and human melanoma cells. Oncogene 2012; 31: 2461–2470.

    Article  CAS  PubMed  Google Scholar 

  60. Kluza J, Corazao-Rozas P, Touil Y, Jendoubi M, Maire C, Guerreschi P et al. Inactivation of the HIF-1alpha/PDK3 signaling axis drives melanoma toward mitochondrial oxidative metabolism and potentiates the therapeutic activity of pro-oxidants. Cancer Res 2012; 72: 5035–5047.

    Article  CAS  PubMed  Google Scholar 

  61. Das Thakur M, Salangsang F, Landman AS, Sellers WR, Pryer NK, Levesque MP et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 2013; 494: 251–255.

    Article  CAS  PubMed  Google Scholar 

  62. Hartsough EJ, Basile KJ, Aplin AE . Beneficial Effects of RAF Inhibitor in Mutant BRAF Splice Variant-Expressing Melanoma. Molecular cancer research: MCR 2014; 12: 795–802.

    Article  CAS  PubMed  Google Scholar 

  63. Gowrishankar K, Snoyman S, Pupo GM, Becker TM, Kefford RF, Rizos H . Acquired resistance to BRAF inhibition can confer cross-resistance to combined BRAF/MEK inhibition. J Invest Dermatol 2012; 132: 1850–1859.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Dermatology, University Hospital Essen, Essen, Germany

    A Roesch

Authors
  1. A Roesch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Roesch.

Ethics declarations

Competing interests

The author declares no conflict of interest

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Roesch, A. Tumor heterogeneity and plasticity as elusive drivers for resistance to MAPK pathway inhibition in melanoma. Oncogene 34, 2951–2957 (2015). https://doi.org/10.1038/onc.2014.249

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2014.249

This article is cited by

Search

Advanced search

Quick links