Response to “Insulin-like growth factor 1 receptor signaling via Akt: a general therapeutic target in neurocutaneous melanocytosis?”

In this issue, Patel et al describe their initial findings on the implications of IGF-IR mediated signaling in the pathophysiology of neurocutaneous melanocytosis (NCM) with special reference to NRAS and BRAF mutations.1 In particular, this study addresses some of the postulations presented in our recent report that suggested the potential of IGF-IR signaling pathway as a target for therapeutics, based on the observation that the inhibition of IGF-IR leads to loss of viability in NCM cells.2 Although it was not shown directly, the downregulation of IGF-binding proteins (IGFBPs) was suggested as a potential mechanism by which NCM cells may enhance their growth and survival potential. However, the lack of variability in the expression levels of IGFBPs among NRAS and BRAF-mutated NCM cells and normal epidermal melanocytes led to the suggestion that lower IGFBPs are a shared characteristic among melanocytic lineage cells that depend on IGF-IR signaling for cell survival and are not a function of their malignant status.1 This has multiple implications for the application of IGF-IR directed therapeutics. It indicates that such targetable cell populations include those carrying the major known mutations, and thus such an approach would be beneficial for most NCM patients. Interestingly, however, the different extent to which the NRAS and BRAF mutant cells are affected by IGF-IR pathway inhibition suggests that a complex relationship may exist between IGF-IR activity and cells with distinct driver mutations. Further studies with more samples and additional knockin or knockout experiments must be done to decipher this possibility. Moreover, because of the pleiotropic nature of IGF-IR mediated pathways in the growth and survival of melanocytes, such studies are inherently complex. This is to some extent reflected in the seemingly diverse findings reported in recent literature, which may be due to the heterogeneity of the cell types studied, the assays utilized, and the models employed.3 Interpatient variations should also be considered because the IGF-IR pathway (ie, the driver) may function only as a bystander in some patients, and the activity status of IGF-IR may influence only at a distinct phase of its molecular or clinical evolution. It is also uncertain as to what extent the cell culture findings can be translated to provide mechanistic explanations for the tumor biology in vivo. However, while the specifics still remain to be elucidated, there is general agreement on the important role played by IGF-IR mediated processes in the oncogenesis of melanocytic tumors.4–7 The identification of Akt as a nodal point in the convergence of activation signals from key mutations and IGF-IR, which may push melanocytic cells through stages of cell cycle, provides strategies to deal with genomic events that are presently not directly actionable.8 Overall, the preliminary report by Patel et al provides an interesting conceptualization of recent findings (including our report) and presents a lead into a key area for future research to identify effective targeted therapeutics for one of the most difficult- to-cure malignancies in medicine. Conflict of interest statement. The authors declare no conflict of interest.

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