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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Prognostic Value of Beta-Tubulin-3 and c-Myc in Muscle Invasive Urothelial Carcinoma of the Bladder
Francesco Massari,Emilio Bria,Chiara Ciccarese,Enrico Munari,Alessandra Modena,Valentina Zambonin,Isabella Sperduti,Walter Artibani,Liang Cheng,Guido Martignoni,Giampaolo Tortora,Matteo Brunelli +11 more
TL;DR: In this paper, the expression of beta-tubulin-3 and c-Myc was evaluated to determine their prognostic potential for bladder urothelial carcinoma in 46 patients.
Patent
Max binders as myc modulators and uses thereof
Angela N. Koehler,Eric Stefan,Francisco Caballero,Dylan V. Neel,Nicholas B. Struntz,Helen L. Evans,Andrew Chen +6 more
TL;DR: In this paper, the MAX binders and/or modulators of Myc, Mad, or Mxi1 (e.g., inhibitors of myc, mad, or mxi1) were described and methods of using and uses of the compounds, compositions, and kits.
SHORT COMMUNICATION Kras G12D induces EGFR-MYC cross signaling in murine primary pancreatic ductal epithelial cells
S Diersch,M Wirth,Christian Schneeweis,F Geisler,JT Siveke,R Rad,Roland M Schmid,D Saur,AK Rustgi,M Reichert,G Schneider +10 more
Journal ArticleDOI
A New Insight into MYC Action: Control of RNA Polymerase II Methylation and Transcription Termination
TL;DR: The data point to a MYC/ PRMT5/RNAPII axis that controls termination via RNAPII dimethylation (R1810me2s) and may contribute to fine-tune the expression of genes altered by MYC overexpression in cancer cells, it remains to be seen which role this may have in tumor development and maintenance.
Posted ContentDOI
Acidic fibroblast growth factor underlies microenvironmental regulation of MYC in pancreatic cancer
Sohinee Bhattacharyya,Chet Oon,Aayush Kothari,Wesley Horton,Jason Link,Rosalie C. Sears,Mara H. Sherman +6 more
TL;DR: It is demonstrated that acidic fibroblast growth factor (FGF1) derived from cancer-associated fibroblasts (CAFs) cooperates with cancer cell-autonomous signals to increase MYC level, promoter occupancy, and activity, and establishes CAF-derived FGF1 as a novel paracrine regulator of oncogenic transcription.
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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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