NOVEL MOLECULAR TARGETS IN MALIGNANT MELANOMA: BRAF AND BEYOND

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

References

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