MYC as a Target for Cancer Treatment: from Undruggable to Druggable?

Abstract

MYC is one of the most frequently altered genes in cancer with an estimated 70% prevalence of deregulation. Deregulated MYC is believed to promote cancer formation/progression via multiple mechanisms including tumour cell intrinsic mechanisms, altering the tumour microenvironment and promoting host immune suppression. Owing to the high prevalence of alterations and its causative role in tumorigenesis, MYC is a highly attractive target for new anticancer therapies. However, as MYC lacks a readily identifiably pocket for potential low molecular weight inhibitors and is predominantly located in the cell nucleus, it has proved difficult to target using standard pharmacological approaches. Recently, however, these problems appear to have been successfully resolved, with the discovery of promising anti-MYC compounds such as Omomyc or MYCi975. Both Omomyc and MYCi975 exhibit anti-cancer activity in several different animal models, with apparently little short-term toxicity. Furthermore, consistent with the ability of MYC to promote a pro-tumour microenvironment and induce immune evasion, treatment with Omomyc or MYCi975 was shown to increase uptake of anti-tumour lymphocytes and enhance response to immunotherapy. Currently, at least five anti-MYC compounds are being evaluated for potential anti-cancer activity in clinical trials. Results from a phase I trial with OMO-103 (a form of Omomyc) suggest that the inhibitor is well tolerated, with most of its adverse effects being at grade 1 level. Evidence of target inhibition was the finding of decreased expression of multiple MYC regulated genes.