Omomyc is a dominant-negative MYC mutant that has previously been shown to attenuate MYC-dependent gene transcription. The authors generated mice (Tre–Omomyc;CMVrtTA) in which Omomyc expression was controlled by a tetracycline-responsive promoter element (Tre) and the rtTA transactivator from the promiscuous cytomegalovirus (CMV) early promoter, resulting in high Omomyc expression in multiple tissues following the administration of doxycyclin. Although sustained treatment with doxycyclin for 4 weeks significantly attenuated proliferation in rapidly dividing tissues such as testis, skin and intestinal crypts, the mice exhibited no outward signs of distress or disease. Moreover, all observed pathologies were rapidly reversed following doxycyclin withdrawal. So, although the side-effects of MYC inhibition are significant, they appear to be well-tolerated and, more importantly, readily reversible.
The next challenge was to show that interference with MYC activity had a discernable effect on tumour growth. To do this, the authors used the well-established LSL–KrasG12D murine model. In these mice, the inhalation of adenovirus expressing Cre recombinase triggers oncogenic KRASG12D expression in bronchioalveolar ductal junction (BADJ) epithelial cells, resulting in lung tumour development. However, LSL–KrasG12D; Tre–Omomyc;CMVrtTA mice expressing Omomyc failed to develop tumours following intranasal administration of adenoviral Cre, and closer examination of these mice showed reduced proliferation of cells at the BADJs. Next, Omomyc expression was induced in mice that had been expressing KRASG12D for 6 weeks. This resulted in dramatic tumour shrinkage, and residual lesions displayed high levels of apoptosis. Together, these experiments support a requirement for endogenous MYC in early-stage KRASG12D-induced tumour establishment and maintenance, but would MYC inhibition have any effect in animals with more advanced disease? The authors sustained KRASG12D expression for 18 weeks before activating Omomyc. All mice examined developed lung tumours, many of which were large, highly vascularized adenocarcinomas. However, as little as 3 days of Omomyc expression resulted in profound tumour shrinkage and, by 28 days, animals were tumour-free.
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