Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice
Laura Soucek,Laura Soucek,Jonathan Whitfield,Jonathan Whitfield,Nicole M. Sodir,Nicole M. Sodir,Daniel Massó-Vallés,Erika Serrano,Anthony N. Karnezis,Lamorna Brown Swigart,Gerard I. Evan,Gerard I. Evan +11 more
TLDR
It is demonstrated that metronomic Myc inhibition not only contains Ras-driven lung tumors indefinitely, but also leads to their progressive eradication, endorsing Myc as a compelling cancer drug target.Abstract:
The principal reason for failure of targeted cancer therapies is the emergence of resistant clones that regenerate the tumor. Therapeutic efficacy therefore depends on not only how effectively a drug inhibits its target, but also the innate or adaptive functional redundancy of that target and its attendant pathway. In this regard, the Myc transcription factors are intriguing therapeutic targets because they serve the unique and irreplaceable role of coordinating expression of the many diverse genes that, together, are required for somatic cell proliferation. Furthermore, Myc expression is deregulated in most—perhaps all—cancers, underscoring its irreplaceable role in proliferation. We previously showed in a preclinical mouse model of non-small-cell lung cancer that systemic Myc inhibition using the dominant-negative Myc mutant Omomyc exerts a dramatic therapeutic impact, triggering rapid regression of tumors with only mild and fully reversible side effects. Using protracted episodic expression of Omomyc, we now demonstrate that metronomic Myc inhibition not only contains Ras-driven lung tumors indefinitely, but also leads to their progressive eradication. Hence, Myc does indeed serve a unique and nondegenerate role in lung tumor maintenance that cannot be complemented by any adaptive mechanism, even in the most aggressive p53-deficient tumors. These data endorse Myc as a compelling cancer drug target.read more
Citations
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References
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Journal ArticleDOI
The Action Mechanism of the Myc Inhibitor Termed Omomyc May Give Clues on How to Target Myc for Cancer Therapy
M. Savino,Daniela Annibali,Nicoletta Carucci,Emilia Favuzzi,Michael D. Cole,Gerard I. Evan,Laura Soucek,Sergio Nasi +7 more
TL;DR: It is suggested that successfully targeting Myc for cancer therapy might require a similar twofold action, in order to prevent Myc/Max binding to E-boxes and, at the same time, keep repressing genes that would be repressed by Myc.
Journal ArticleDOI
Tristetraprolin Impairs Myc-Induced Lymphoma and Abolishes the Malignant State
Robert J. Rounbehler,Mohammad Fallahi,Chunying Yang,Meredith A. Steeves,Weimin Li,Joanne R. Doherty,Franz X. Schaub,Sandhya Sanduja,Dan A. Dixon,Perry J. Blackshear,John L. Cleveland +10 more
TL;DR: There is a selection for TTP loss in malignancy; thus, TTP functions as a tumor suppressor and Myc/TTP-directed control of select cancer-associated ARED genes is disabled during lymphomagenesis.
Journal ArticleDOI
Omomyc expression in skin prevents Myc-induced papillomatosis.
TL;DR: It is shown that it is possible to selectively enhance the intrinsic apoptotic pathway mediated by Myc and so quell its oncogenic action, and restore the normal keratinocyte differentiation program and skin architecture, both of which are otherwise disrupted by MyC activation.
Journal ArticleDOI
Cancer incidence in patients with polyglutamine diseases: a population-based study in Sweden.
TL;DR: The consistently decreased incidence of cancer in patients with polyQ diseases suggests that a common mechanism protects against the development of cancer.
Journal ArticleDOI
Mouse Models of Human Non-Small-Cell Lung Cancer: Raising the Bar
Carla F. Kim,E. L. Jackson,David G. Kirsch,David G. Kirsch,Jan Grimm,Alice T. Shaw,Alice T. Shaw,Keara Michelle Lane,Joseph L. Kissil,Kenneth P. Olive,Alejandro Sweet-Cordero,Ralph Weissleder,Tyler Jacks,Tyler Jacks +13 more
TL;DR: Improved conditional mouse models are now available as tools to improve the understanding of the cellular and molecular origins of adenocarcinoma and Integrated thinking to apply technological advances while using the appropriate mouse model is likely to facilitate discoveries that will significantly improve lung cancer detection and intervention.
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