Paradoxical oncogenesis--the long-term effects of BRAF inhibition in melanoma

Abstract

The clinical benefits of BRAF inhibition in patients with advanced-stage BRAF-mutant melanoma are now well established. Although the emergence of cutaneous squamous-cell carcinomas (SCCs) and secondary melanomas in patients on BRAF-inhibitor therapy have been well described, reports are emerging of additional secondary premalignant and malignant events, including RAS-mutant leukaemia, the metastatic recurrence of RAS-mutant colorectal cancer and the development of gastric and colonic polyps. In most cases, paradoxical MAPK activation--resulting from the BRAF-inhibitor-mediated homodimerization and heterodimerization of nonmutant RAF isoforms--seems to underlie the development of these secondary tumours. Although evidence supports that therapy with the simultaneous administration of BRAF and MEK inhibitors abrogates the onset of treatment-induced SCCs, whether combination treatment will limit the emergence of all BRAF-inhibitor-driven pathologies is unclear. In this Review, we describe the clinical and mechanistic manifestations of secondary cancers that have thus far been observed to arise as a consequence of BRAF inhibition. We discuss the concept of pre-existing populations of partly transformed cells with malignant potential that might be present in various organ systems, and the rationale for novel therapeutic strategies for the management of BRAF-inhibitor-induced neoplasia.

Figure 1

RAF activation of the MAPK/ERK pathway. Under normal conditions, the growth signalling cascades are initiated through binding of growth factors to growth factor receptor tyrosine kinase receptors at the cell surface. The GTPase RAS is then recruited to the plasma membrane, leading to its activation. RAS binds to and promotes dimer formation of the RAF family of kinases, a process crucial for kinase activation and downstream signal transduction.

Figure 2

Paradoxical activation of the MAPK/ERK pathway in tumours treated with RAF inhibitors. a | In cells with mutant RAS, BRAF is typically sequestered in the cytosol and is kept inactive either through autophosphorylation or by phophorylating another protein that keeps it in an inactive state. One study has demonstrated that inhibiting BRAF in the presence of a mutated or growth-factor-activated RAS leads to relief of BRAF autoinhibition and, consequently, its recruitment to the plasma membrane where it dimerizes with and hyperactivates CRAF. b | Another suggested mechanism is focused around conformational changes in BRAF and CRAF caused by physical binding of the RAF inhibitor, promoting dimer formation between an uninhibited CRAF protomer and an inhibitor-bound BRAF or CRAF. At low concentrations, the drug binds only one RAF protomer and leads to transactivation of the other. At high concentrations, the drug binds and inhibits both RAF members of the dimer, blocking the signalling complex entirely.^,

Figure 3

Secondary cutaneous skin changes in patients receiving vemurafenib treatment. a | Excoriated and ruptured folliculitis with surrounding granulomatous inflammation. b | Inflamed verruca vulgaris with overlying cutaneous horn. c | Inflamed verruca vulgaris. d | Superficial invasive squamous cell carcinoma arising in association with an inflamed verruca vulgaris. e | Immunohistochemical staining (haematoxylin and eosin)of the lesion from panel d. f | Immunohistochemical staining of the lesion shown in d, indicating expression of phosphorylated ERK in the verruca vulgaris.

Figure 4

MAPK signalling cooperates with loss of APC to promote adenoma development. The tumour suppressive function of APC lies in its ability to bind β-catenin, leading to phosphorylation of β-catenin by GSK3β and its subsequent degradation. Activation of the MAPK/ERK pathway can mediate β-catenin stabilization through ERK-mediated inhibition of GSK3β. Stabilized β-catenin primarily mediates its oncogenic effects through transcriptional activation of target genes such as MYC. Pro-oncogenic MYC is vital for APC-mediated tumorigenesis. ERK can further drive tumour formation in the context of APC loss by stabilizing Myc though post-translational modifications. Abbreviations: MEK, mitogen-activated protein kinase kinase; ERK, extracellular signal-regulated kinase; EGFR, epidermal growth factor receptor; APC, adenomatous polyposis coli; GSK3β, Glycogen synthase kinase-3 beta; Axin, axis inhibition protein.