Konference: 2012 3. pražské mezioborové onkologické kolokvium Prague ONCO

Kategorie: Maligní melanom a nádory kůže

Téma: Review

Číslo abstraktu: 008

Autoři: MUDr. Filip Janků

Recent advances in the treatment of malignant melanoma demonstrate how understanding the molecular foundations of cancer can be quickly translated to rapid improvements in patient care.(1)

Until recently, treatment outcomes in malignant melanoma were dismal.(2) More than two decades of clinical research demonstrated that biochemotherapy is not any better than combination chemotherapy; combined chemotherapy did not fare any better than single agent dacarbazine, which itself had never been compared to best supportive care.(2,3)

Identification of a point mutation in the BRAF gene, which was published in 2002, initiated the molecular era in melanoma treatment.(4) Since then, multiple aberrations have been identified (Table 1). These molecular abnormalities typically lead to constitutive signaling through the mitogen-activated protein kinase (MAPK) pathway, a common molecular feature of many cancers that has been implicated in tumor proliferation, invasion and resistance to apoptosis.(5,6) In addition, tumorigenesis and therapeutic resistance are driven by aberrations in phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling, such as PTEN loss (~20 %) and AKT mutations.(5,7) The MAPK pathway is controlled by RAS protein, which activates numerous downstream effectors, including RAF protein kinase. Once activated, RAF stimulates a MAPK pathway signaling cascade. CRAF is the RAF isoform most critical for mediating RAS signals. CRAF is rarely mutated in human cancer, which led to the discovery of the BRAF V600E mutation as an alternative oncogenic driver in 2002.(4) Patients with melanoma and a BRAF V600E mutation demonstrated unprecedented responses to vemurafenib or GSK2118436, inhibitors of mutated BRAF.(8,9) In contrast, patients with wild-type (wt) BRAF demonstrated accelerated disease progression when treated with vemurafenib. Despite the initial salutary effect of BRAF inhibitors in malignant melanoma with a BRAF mutation, the treatment effects are limited in duration and all patients ultimately progress.(8) Resistance to targeted BRAF inhibition is associated with increased MAPK and/or PI3K/AKT/ mTOR signaling. Molecular aberrations involved in resistance include secondary NRAS mutations, COT amplification, MEK mutations, alternative BRAF splicing, and loss of PTEN function.(7,10-14)

NRAS mutations are usually mutually exclusive with BRAF and they lead to increased MAPK signaling.(15,16) Since direct RAS inhibitors are not known, current strategies focus on MEK inhibitors as targeted therapy for this molecular subset. The data from single agent trials showed prolonged stable disease but no salutary responses as observed in BRAF-mutant melanomas in BRAF inhibitor trials.(17) Anecdotal reports suggest encouraging activity when MEK inhibitors are given in combination with other therapies (unpublished).

Mutations or amplification of KIT are prevalent in acral lentiginous and mucosal melanoma. Early clinical data suggest a salutary effect of KIT inhibitors such as dasatinib when KIT mutation is present.(18) Finally uveal melanoma is associated with frequent mutations in GNAQ or GNA11 oncogenes, which lead to MAPK pathway activation.(19,20) The role of MAPK pathway targeting agents such as MEK inhibitors is currently being evaluated in early-phase clinical trials.

Table 1

Filip Janku, MD, PhD
The University of Texas MD Anderson Cancer Center


  1. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16.
  2. Chapman PB, Einhorn LH, Meyers ML, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 1999;17:2745-51.
  3. Atkins MB, Hsu J, Lee S, et al. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2008;26:5748-54.
  4. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949-54.
  5. Davies MA, Samuels Y. Analysis of the genome to personalize therapy for melanoma. Oncogene 2010;29:5545-55.
  6. Ribas A, Flaherty KT. BRAF targeted therapy changes the treatment paradigm in melanoma. Nat Rev Clin Oncol 2011;8:426-33.
  7. Villanueva J, Vultur A, Lee JT, et al. 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 2010;18:683-95.
  8. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010;363:809-19.
  9. Kefford R, Arkenau H, Brown MP, et al. Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors. J Clin Oncol 2010;28: abstr 8503.
  10. Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 2010;468:973-7.
  11. Johannessen CM, Boehm JS, Kim SY, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 2010;468:968-72.
  12. Wagle N, Emery C, Berger MF, et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2011;29:3085-96.
  13. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 2010;467:596-9.
  14. Janku F, Garrido-Laguna I, Hong DS, et al: PI3K/AKT/mTOR inhibitors in patients with advanced solid tumors and PIK3CA mutations and/or PTEN loss. An AACR Special Conference. Targeting PI3K/mTOR Signaling in Cancer:A56, 2011.
  15. El-Osta H, Falchook G, Tsimberidou A, et al. BRAF mutations in advanced cancers: clinical characteristics and outcomes. PLoS One 6:e25806, 2011.
  16. Jakob JA, Bassett RL, Jr., Ng CS, et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer 2011.
  17. Falchook GS, Infante JR, Fecher LA, et al. The oral MEK 1/2 inhibitor GSK 1120212 demosntrates early efficacy signals. Ann Oncol 2010;21:abstract 4950.
  18. Woodman SE, Trent JC, Stemke-Hale K, et al. Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates. Mol Cancer Ther 2009;8:2079-85.
  19. Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med 2010;363:2191-9.
  20. Van Raamsdonk CD, Bezrookove V, Green G, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 2009; 457:599-602.

Datum přednesení příspěvku: 26. 1. 2012