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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Protein phosphatase 2A activation as a therapeutic strategy for managing MYC-driven cancers
Caroline C. Farrington,Eric Yuan,Sahar Mazhar,Sudeh Izadmehr,Lauren Hurst,Brittany L. Allen-Petersen,Mahnaz Janghorban,Eric Chung,Grace Wolczanski,Matthew D. Galsky,Rosalie C. Sears,Jaya Sangodkar,Goutham Narla +12 more
TL;DR: The findings presented here indicate a pharmacologically tractable approach to drive MYC degradation by using SMAPs for the management of a broad range of MYC-driven cancers.
Journal ArticleDOI
Human UTP14a promotes colorectal cancer progression by forming a positive regulation loop with c-Myc.
Jingyi Zhang,Pengwei Ren,Da Xu,Xiaofeng Liu,Zhenzhen Liu,Chunfeng Zhang,Yuan Li,Lijun Wang,Xiaojuan Du,Baocai Xing +9 more
TL;DR: It is reported that hUTP14a stabilizes c-Myc in colorectal cancer (CRC) progression and forms a complex with USP36/Fbw7γ to inhibit FbW7γ-mediated c- myc degradation, and disruption of hUTp14a-c-MyC regulation may provide a potential therapeutic strategy for a subset of CRC patients.
Journal ArticleDOI
The long journey to bring a Myc inhibitor to the clinic.
Jonathan Whitfield,Laura Soucek +1 more
TL;DR: In this article, the authors pay homage to the different strategies developed so far against Myc and all of the researchers focused on developing treatments for a target long deemed undruggable.
Journal ArticleDOI
MYC regulates ribosome biogenesis and mitochondrial gene expression programs through its interaction with host cell factor-1.
Tessa M. Popay,Jing Wang,Clare M. Adams,Gregory C. Howard,Simona G. Codreanu,Stacy D. Sherrod,John A. McLean,Lance R. Thomas,Shelly L. Lorey,Yuichi J. Machida,April M. Weissmiller,Christine M. Eischen,Qi Liu,William P. Tansey +13 more
TL;DR: Popay et al. as mentioned in this paper showed that if anti-cancer drugs were able to target HCF-1 proteins, they could potentially reduce or even reverse the growth of tumours.
Journal ArticleDOI
Small molecule selectively suppresses MYC transcription in cancer cells
Claire Bouvard,Sang Min Lim,John Ludka,Nahid Yazdani,Ashley K. Woods,Arnab Chatterjee,Peter G. Schultz,Shoutian Zhu +7 more
TL;DR: It is demonstrated that a pharmacological agent, stauprimide, selectively suppresses MYC transcription in a variety of cancer cells in vitro and inhibits tumor growth in xenograft mouse models and evidence is provided to support further development of stauPrimide as an anticancer drug candidate.
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
TL;DR: The results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.
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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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