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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FOXR2 Interacts with MYC to Promote Its Transcriptional Activities and Tumorigenesis
TL;DR: Results indicate that FOXR2 acts with MYC to promote cancer cell proliferation, which is a potential tumor-specific target for therapeutic intervention against MYC-driven cancers.
Journal ArticleDOI
Critical role of Myc activation in mouse hepatocarcinogenesis induced by the activation of AKT and RAS pathways
Bing Xin,Masahiro Yamamoto,Kiyonaga Fujii,Takako Ooshio,Xi Chen,Yoko Okada,Kenji Watanabe,Naoyuki Miyokawa,Hiroyuki Furukawa,Yuji Nishikawa +9 more
TL;DR: The results demonstrate that in hepatocarcinogenesis induced by both activated AKT and HRAS, activation of endogenous Myc is an enhancing factor and adequate levels of Myc deregulation further facilitate the process with alterations in cellular metabolism.
Journal ArticleDOI
Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells
Christoph Otto,Stefanie Schmidt,C. Kastner,Sarah Denk,J. Kettler,Nora Müller,Christoph-Thomas Germer,Elmar Wolf,Peter Gallant,Armin Wiegering +9 more
TL;DR: The findings suggest that inhibition of BRD4 by JQ1 and degradation of BRd4 by dBET1 and MZ1 are powerful tools for reducing MYC expression and CRC cell proliferation.
Journal ArticleDOI
Targeting Antitumoral Proteins to Breast Cancer by Local Administration of Functional Inclusion Bodies
Mireia Pesarrodona,Toni Jauset,Zamira V. Díaz-Riascos,Alejandro Sánchez-Chardi,Marie-Eve Beaulieu,Joaquin Seras-Franzoso,Laura Sánchez-García,Ricardo Baltá-Foix,Sandra Mancilla,Yolanda Fernández,Ursula Rinas,Simó Schwartz,Laura Soucek,Antonio Villaverde,Ibane Abasolo,Esther Vázquez +15 more
TL;DR: These findings support the concept of bacterial inclusion bodies as versatile protein materials suitable for application in chronic diseases that, like cancer, can benefit from a local slow release of therapeutic proteins.
Journal ArticleDOI
High expression of RAD51 promotes DNA damage repair and survival in KRAS-mutant lung cancer cells.
TL;DR: The results suggest that mutant KRAS promotes RAD51 expression to enhance DNA damage repair and lung cancer cell survival, suggesting that RAD51 may be an effective therapeutic target to overcome chemo/radioresistance in KRAS mutant cancers.
References
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Journal ArticleDOI
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.
Journal ArticleDOI
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.
Journal ArticleDOI
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.
Journal ArticleDOI
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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