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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Challenges with the discovery of RNA-based therapeutics for flaviviruses
TL;DR: In this article , the authors briefly introduced the biology of flaviviruses and the current advances in RNA-based therapeutics for them, and listed the challenges and possible solutions in this area.
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Circadian disruption enhances HSF1 signaling and tumorigenesis in Kras-driven lung cancer
TL;DR: In this paper , the authors demonstrate that exposure to chronic circadian disruption (chronic jetlag, CJL) increases tumor burden in a mouse model of KRAS-driven lung cancer, and implicate HSF1 as a molecular link between circadian disruption and enhanced tumorigenesis.
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Reducing MYC's transcriptional footprint unveils a good prognostic gene signature in melanoma
Mariano F. Zacarias-Fluck,Daniel Massó-Vallés,Fabio Giuntini,I. González-Larreategui,J. Kaur,Sílvia Casacuberta-Serra,Toni Jauset,Sandra Martínez-Martín,Génesis Martín-Fernández,Erika Serrano del Pozo,Laia Foradada,Judit Grueso,Lara Nonell,Marie-Eve Beaulieu,Jonathan Whitfield,Laura Soucek +15 more
TL;DR: Zacarías-Fluck et al. as mentioned in this paper reported the use of Omomyc, a MYC inhibitor, in targeting melanoma development, metastasis, and recurrence in human cell lines and CDX mouse models.
Journal ArticleDOI
myc Gene and Cancer Variant Analysis and Network Interaction: An In-Silico Analysis
TL;DR: Proteins involved in myc ’s post-translational modulation have been identified as significant surrogate targets for lowering myc activity downstream of aberrant cell stimulatory signals.
Book ChapterDOI
An "-omycs" Toolbox to Work with MYC.
Jonathan Whitfield,Laura Soucek +1 more
TL;DR: The Myc gene: Methods and Protocols as discussed by the authors provides valuable tips from key "inhabitants of the MYC world", which significantly increase the reach of our investigative tools to shed light on the mysteries still surrounding MYC.
References
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BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc
Jake Delmore,Ghayas C Issa,Madeleine E. Lemieux,Peter B. Rahl,Junwei Shi,Hannah M. Jacobs,Efstathios Kastritis,Timothy Gilpatrick,Ronald M. Paranal,Jun Qi,Marta Chesi,Anna C. Schinzel,Michael R. McKeown,Timothy P. Heffernan,Christopher R. Vakoc,P. Leif Bergsagel,Irene M. Ghobrial,Paul G. Richardson,Richard A. Young,William C. Hahn,William C. Hahn,Kenneth C. Anderson,Andrew L. Kung,James E. Bradner,Constantine S. Mitsiades +24 more
TL;DR: In this paper, a small-molecule bromodomain inhibitor, JQ1, was used to identify BET proteins as regulatory factors for c-Myc oncoprotein.
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Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras
Erica L. Jackson,Nicholas A. Willis,Kim L. Mercer,Roderick T. Bronson,Denise Crowley,Raymond Montoya,Tyler Jacks,David A. Tuveson +7 more
TL;DR: It is shown that the use of a recombinant adenovirus expressing Cre recombinase (AdenoCre) to induce K-ras G12D expression in the lungs of mice allows control of the timing and multiplicity of tumor initiation.
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RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia
Johannes Zuber,Junwei Shi,Junwei Shi,Eric Wang,Amy R. Rappaport,Amy R. Rappaport,Harald Herrmann,Edward Allan R. Sison,Daniel Magoon,Jun Qi,Katharina Blatt,Mark Wunderlich,Meredith J. Taylor,Christopher Johns,Agustin Chicas,James C. Mulloy,Scott C. Kogan,Patrick Brown,Peter Valent,James E. Bradner,Scott W. Lowe,Scott W. Lowe,Scott W. Lowe,Christopher R. Vakoc +23 more
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Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects
David A. Tuveson,Alice T. Shaw,Alice T. Shaw,Alice T. Shaw,Nicholas A. Willis,Daniel P. Silver,Erica L. Jackson,Sandy Chang,Kim L. Mercer,Rebecca Grochow,Hanno Hock,Denise Crowley,Sunil R. Hingorani,Tal Z. Zaks,Catrina King,Michael A. Jacobetz,Lifu Wang,Roderick T. Bronson,Stuart H. Orkin,Stuart H. Orkin,Ronald A. DePinho,Tyler Jacks +21 more
TL;DR: It is demonstrated that the conditional expression of an endogenous K-ras(G12D) allele in murine embryonic fibroblasts causes enhanced proliferation and partial transformation in the absence of further genetic abnormalities.
Journal ArticleDOI
Modelling Myc inhibition as a cancer therapy
Laura Soucek,Jonathan Whitfield,Carla P. Martins,Andrew J. Finch,Daniel J. Murphy,Nicole M. Sodir,Anthony N. Karnezis,Lamorna Brown Swigart,Sergio Nasi,Gerard I. Evan +9 more
TL;DR: It is shown 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.
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