Modelling Myc inhibition as a cancer therapy

Abstract

The Myc gene encodes for a transcription factor that is central to gene regulation in normal cells. It is also an oncogene, overexpressed or amplified in many different types of tumour. Though this makes it a candidate target for antitumour drugs, its involvement in many normal cell functions, lack of evidence of therapeutic efficacy and the difficulty of targeting it mean that it is not top of many lists of potential targets. That could change. Using a mouse model of Ras-dependent lung cancer in which Myc function can in effect be turned on and off, Soucek et al. show that inhibition of endogenous Myc triggers tumour regression. Significantly, although systemic inhibition of Myc has effects in other tissues, these were readily reversible, suggesting that Myc might be a valid anticancer target. c-Myc acts as oncogen in many tumours, often due to its amplification and/or overexpression. This study investigates whether inhibition of endogenous Myc in tumours driven by other oncogenes may also interfere with tumour growth. This was found to be the case. Although systemic inhibition of Myc has effects in other tissues, these were found to be reversible, suggesting that Myc might be a valid anti-cancer target. Myc is a pleiotropic basic helix–loop–helix leucine zipper transcription factor that coordinates expression of the diverse intracellular and extracellular programs that together are necessary for growth and expansion of somatic cells1. In principle, this makes inhibition of Myc an attractive pharmacological approach for treating diverse types of cancer. However, enthusiasm has been muted by lack of direct evidence that Myc inhibition would be therapeutically efficacious, concerns that it would induce serious side effects by inhibiting proliferation of normal tissues, and practical difficulties in designing Myc inhibitory drugs. We have modelled genetically both the therapeutic impact and the side effects of systemic Myc inhibition in a preclinical mouse model of Ras-induced lung adenocarcinoma by reversible, systemic expression of a dominant-interfering Myc mutant. We show that Myc inhibition triggers rapid regression of incipient and established lung tumours, defining an unexpected role for endogenous Myc function in the maintenance of Ras-dependent tumours in vivo. Systemic Myc inhibition also exerts profound effects on normal regenerating tissues. However, these effects are well tolerated over extended periods and rapidly and completely reversible. Our data demonstrate the feasibility of targeting Myc, a common downstream conduit for many oncogenic signals, as an effective, efficient and tumour-specific cancer therapy.