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Modelling Myc inhibition as a cancer therapy

Abstract

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.

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Figure 1: Endogenous Myc function is required for formation and maintenance of early-stage Kras-induced lung hyperplasias/adenomas.
Figure 2: Myc inhibition elicits regression of established lung tumours.
Figure 3: Inhibition of endogenous Myc suppresses proliferation in skin, testis and GI tract.
Figure 4: The degenerative phenotypes induced by systemic Myc inhibition are rapidly and completely reversible on restoration of Myc function.

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Acknowledgements

We thank T. Jacks and S. Artandi for their gifts of LSL-KrasG12D and β-actin-rtTA+ mice, respectively. We thank F. Rostker for technical assistance and Y. Yaron and L. Johnson for advice on the LSL-KrasG12D model and adenovirus inhalation. We thank our laboratory colleagues for their comments and feedback. This study was supported by grant 2R01 CA98018 from the National Cancer Institute (to G.I.E.). S.N. acknowledges support from AIRC, ASI, CNR, MIUR FIRB and FIRS. C.P.M. is a Leukemia and Lymphoma Society Fellow. J.W. acknowledges support from Human Frontier Science Program. This paper is dedicated to the memory of Judah Folkman.

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Correspondence to Gerard I. Evan.

Supplementary information

Supplementary Information

The file contains Supplementary Figures and Legends 1-4; Supplementary Tables 1-3. Supplementary Figure 1 represents quantitation of Omomyc and c-Myc expression in mouse tissues; Supplementary Figure 2 shows no influence of long-term systemic Omomyc expression on mouse weight; Supplementary. Figure 3 demonstrates that systemic Omomyc expression suppresses hair re-growth; Supplementary Figure 4 shows that induction of Omomyc in TRE-Omomyc; β-actin-rtTA mice recapitulates the intestinal and skin phenotypes of Doxycylin treated TREOmomyc;CMVrtTA mice and, additionally, elicits increased extramedullary hematopoiesis in spleen. Supplementary Table 1 shows that long-term systemic Omomyc expression has no significant impact on blood chemistry; Supplementary Table 2 includes blood counts showing that Omomyc expression causes transient anemia; Supplementary Table 3 includes detailed list of number and genotype of mice used for the experiments. (PDF 14691 kb)

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Soucek, L., Whitfield, J., Martins, C. et al. Modelling Myc inhibition as a cancer therapy. Nature 455, 679–683 (2008). https://doi.org/10.1038/nature07260

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