MYC cooperates with AKT in prostate tumorigenesis and alters sensitivity to mTOR inhibitors.
Nicola J. Clegg,Suzana S. Couto,John Wongvipat,Haley Hieronymus,Brett S. Carver,Barry S. Taylor,Katharine Ellwood-Yen,William L. Gerald,Chris Sander,Charles L. Sawyers +9 more
TLDR
Bigenic mice generated in which both activated human AKT1 and human MYC are expressed in the prostate showed reduced sensitivity to mTOR inhibition, suggesting that additional genetic events may dampen mTOR dependence, and these data have implications for treatment of human prostate cancers with PI3K-pathway alterations using mTOR inhibitors.Abstract:
MYC and phosphoinositide 3-kinase (PI3K)-pathway deregulation are common in human prostate cancer. Through examination of 194 human prostate tumors, we observed statistically significant co-occurrence of MYC amplification and PI3K-pathway alteration, raising the possibility that these two lesions cooperate in prostate cancer progression. To investigate this, we generated bigenic mice in which both activated human AKT1 and human MYC are expressed in the prostate (MPAKT/Hi-MYC model). In contrast to mice expressing AKT1 alone (MPAKT model) or MYC alone (Hi-MYC model), the bigenic phenotype demonstrates accelerated progression of mouse prostate intraepithelial neoplasia (mPIN) to microinvasive disease with disruption of basement membrane, significant stromal remodeling and infiltration of macrophages, B- and T-lymphocytes, similar to inflammation observed in human prostate tumors. In contrast to the reversibility of mPIN lesions in young MPAKT mice after treatment with mTOR inhibitors, Hi-MYC and bigenic MPAKT/Hi-MYC mice were resistant. Additionally, older MPAKT mice showed reduced sensitivity to mTOR inhibition, suggesting that additional genetic events may dampen mTOR dependence. Since increased MYC expression is an early feature of many human prostate cancers, these data have implications for treatment of human prostate cancers with PI3K-pathway alterations using mTOR inhibitors.read more
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Journal ArticleDOI
MYC Activation Is a Hallmark of Cancer Initiation and Maintenance
TL;DR: Tumors appear to be "addicted" to MYC because of both tumor cell-intrinsic, cell-autonomous and host-dependent, immune cell-dependent mechanisms.
Journal ArticleDOI
ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss.
Yu Chen,Ping Chi,Shira Rockowitz,Phillip J. Iaquinta,Tambudzai Shamu,Shipra Shukla,Dong Gao,Inna Sirota,Brett S. Carver,John Wongvipat,Howard I. Scher,Deyou Zheng,Charles L. Sawyers,Charles L. Sawyers +13 more
TL;DR: A new conditional mouse model is described that shows robust, homogenous ERG expression throughout the prostate, suggesting that ETS factors cause prostate-specific transformation by altering the AR cistrome, priming the prostate epithelium to respond to aberrant upstream signals such as PTEN loss.
Book ChapterDOI
Oncogenic Roles of the PI3K/AKT/mTOR Axis
Masahiro Aoki,Teruaki Fujishita +1 more
TL;DR: Possible mechanisms by which the PI3K/AKT/mTOR axis contributes to oncogenic transformation include stimulation of proliferation, survival, metabolic reprogramming, and invasion/metastasis, as well as suppression of autophagy and senescence.
Journal ArticleDOI
Animal models of human prostate cancer: The consensus report of the new york meeting of the mouse models of human cancers consortium prostate pathology committee
Michael Ittmann,Jiaoti Huang,Enrico Radaelli,Philip Martin,Sabina Signoretti,Ruth Sullivan,Brian W. Simons,Jerrold M. Ward,Brian D. Robinson,Gerald C. Chu,Massimo Loda,George Thomas,Alexander D. Borowsky,Robert D. Cardiff +13 more
TL;DR: Analysis of multiple genetically engineered models has shown that reactive stroma formation is present in all the models developing invasive carcinomas, and this promises to enhance development of new approaches to prevention, detection, and treatment of this common malignancy.
Journal ArticleDOI
Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway
Yu-Ru Lee,Yu-Ru Lee,Ming Chen,Ming Chen,Jonathan D. Lee,Jonathan D. Lee,Jinfang Zhang,Shu-Yu Lin,Tian-Min Fu,Tian-Min Fu,Hao Chen,Hao Chen,Tomoki Ishikawa,Tomoki Ishikawa,Shang Yin Chiang,Shang Yin Chiang,Jesse Katon,Jesse Katon,Yang Zhang,Yang Zhang,Yulia V. Shulga,Yulia V. Shulga,Assaf C. Bester,Assaf C. Bester,Jacqueline Fung,Jacqueline Fung,Emanuele Monteleone,Emanuele Monteleone,Emanuele Monteleone,Lixin Wan,Chen Shen,Chen Shen,Chih-Hung Hsu,Chih-Hung Hsu,Chih-Hung Hsu,Antonella Papa,John G. Clohessy,John G. Clohessy,Julie Teruya-Feldstein,Suresh Jain,Hao Wu,Hao Wu,Lydia E. Matesic,Ruey-Hwa Chen,Ruey-Hwa Chen,Wenyi Wei,Pier Paolo Pandolfi,Pier Paolo Pandolfi +47 more
TL;DR: It is found that WWP1 may be transcriptionally activated by the MYC proto-oncogene and that genetic depletion of Wwp1 in both Myc-driven mouse models of prostate cancer in vivo and cancer cells in vitro reactivates PTEN function, leading to inhibition of the PI3K-AKT pathway and MYC-driven tumorigenesis.
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TL;DR: The interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated gliobeasts, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.
Journal ArticleDOI
The phosphatidylinositol 3-Kinase AKT pathway in human cancer.
Igor Vivanco,Charles L. Sawyers +1 more
TL;DR: Small-molecule therapeutics that block PI3K signalling might deal a severe blow to cancer cells by blocking many aspects of the tumour-cell phenotype.
Journal ArticleDOI
Integrative genomic profiling of human prostate cancer
Barry S. Taylor,Nikolaus Schultz,Haley Hieronymus,Anuradha Gopalan,Yonghong Xiao,Brett S. Carver,Vivek K. Arora,Poorvi Kaushik,Ethan Cerami,Boris Reva,Yevgeniy Antipin,Nicholas Mitsiades,Thomas Landers,Igor Dolgalev,John E. Major,Manda Wilson,Nicholas D. Socci,Alex E. Lash,Adriana Heguy,James A. Eastham,Howard I. Scher,Victor E. Reuter,Peter T. Scardino,Chris Sander,Charles L. Sawyers,Charles L. Sawyers,William L. Gerald +26 more
TL;DR: Analysis of genomic and clinical outcome data from 218 prostate cancer tumors revealed that copy-number alterations robustly define clusters of low- and high-risk disease beyond that achieved by Gleason score.
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