33 results on '"Kevin Marks"'
Search Results
2. Supplementary Table S1.1 from Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in LKB1-Mutant Lung Cancer
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Kwok-Kin Wong, Lewis C. Cantley, David E. Root, Nathanael S. Gray, Andrew L. Kung, William Y. Kim, David J. Kwiatkowski, John V. Heymach, Ignacio I. Wistuba, Don L. Gibbons, Lauren A. Byers, Alec Kimmelman, Ralph Scully, John M. Asara, Reuben J. Shaw, Brendan D. Manning, Jeffrey A. Engelman, Nabeel Bardeesy, Pasi A. Janne, Nirali M. Patel, D. Neil Hayes, Norman E. Sharpless, Sean T. Bailey, Jianming Zhang, Edward M. Driggers, Sung Choe, Xiaoxu Wang, Jeremy H. Tchaicha, Abigail B. Altabef, Zhao Chen, Yong Zhang, Peng Gao, Travis J. Cohoon, Chunxiao Xu, Thomas J.F. Nieland, Qingsong Liu, Julian Carretero, Glenn S. Cowley, Kevin Marks, and Yan Liu
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Top 100 shRNAs.
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- 2023
3. Supplementary Table S1.4 from Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in LKB1-Mutant Lung Cancer
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Kwok-Kin Wong, Lewis C. Cantley, David E. Root, Nathanael S. Gray, Andrew L. Kung, William Y. Kim, David J. Kwiatkowski, John V. Heymach, Ignacio I. Wistuba, Don L. Gibbons, Lauren A. Byers, Alec Kimmelman, Ralph Scully, John M. Asara, Reuben J. Shaw, Brendan D. Manning, Jeffrey A. Engelman, Nabeel Bardeesy, Pasi A. Janne, Nirali M. Patel, D. Neil Hayes, Norman E. Sharpless, Sean T. Bailey, Jianming Zhang, Edward M. Driggers, Sung Choe, Xiaoxu Wang, Jeremy H. Tchaicha, Abigail B. Altabef, Zhao Chen, Yong Zhang, Peng Gao, Travis J. Cohoon, Chunxiao Xu, Thomas J.F. Nieland, Qingsong Liu, Julian Carretero, Glenn S. Cowley, Kevin Marks, and Yan Liu
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70 genes selected for validation.
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- 2023
4. Supplementary Table S1.3 from Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in LKB1-Mutant Lung Cancer
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Kwok-Kin Wong, Lewis C. Cantley, David E. Root, Nathanael S. Gray, Andrew L. Kung, William Y. Kim, David J. Kwiatkowski, John V. Heymach, Ignacio I. Wistuba, Don L. Gibbons, Lauren A. Byers, Alec Kimmelman, Ralph Scully, John M. Asara, Reuben J. Shaw, Brendan D. Manning, Jeffrey A. Engelman, Nabeel Bardeesy, Pasi A. Janne, Nirali M. Patel, D. Neil Hayes, Norman E. Sharpless, Sean T. Bailey, Jianming Zhang, Edward M. Driggers, Sung Choe, Xiaoxu Wang, Jeremy H. Tchaicha, Abigail B. Altabef, Zhao Chen, Yong Zhang, Peng Gao, Travis J. Cohoon, Chunxiao Xu, Thomas J.F. Nieland, Qingsong Liu, Julian Carretero, Glenn S. Cowley, Kevin Marks, and Yan Liu
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Top 200 genes by W2ndB.
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- 2023
5. Supplementary Methods, Figure Legends from Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in LKB1-Mutant Lung Cancer
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Kwok-Kin Wong, Lewis C. Cantley, David E. Root, Nathanael S. Gray, Andrew L. Kung, William Y. Kim, David J. Kwiatkowski, John V. Heymach, Ignacio I. Wistuba, Don L. Gibbons, Lauren A. Byers, Alec Kimmelman, Ralph Scully, John M. Asara, Reuben J. Shaw, Brendan D. Manning, Jeffrey A. Engelman, Nabeel Bardeesy, Pasi A. Janne, Nirali M. Patel, D. Neil Hayes, Norman E. Sharpless, Sean T. Bailey, Jianming Zhang, Edward M. Driggers, Sung Choe, Xiaoxu Wang, Jeremy H. Tchaicha, Abigail B. Altabef, Zhao Chen, Yong Zhang, Peng Gao, Travis J. Cohoon, Chunxiao Xu, Thomas J.F. Nieland, Qingsong Liu, Julian Carretero, Glenn S. Cowley, Kevin Marks, and Yan Liu
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Supplementary Methods, Figure Legends
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- 2023
6. Supplementary Figures S1- S10 from Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in LKB1-Mutant Lung Cancer
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Kwok-Kin Wong, Lewis C. Cantley, David E. Root, Nathanael S. Gray, Andrew L. Kung, William Y. Kim, David J. Kwiatkowski, John V. Heymach, Ignacio I. Wistuba, Don L. Gibbons, Lauren A. Byers, Alec Kimmelman, Ralph Scully, John M. Asara, Reuben J. Shaw, Brendan D. Manning, Jeffrey A. Engelman, Nabeel Bardeesy, Pasi A. Janne, Nirali M. Patel, D. Neil Hayes, Norman E. Sharpless, Sean T. Bailey, Jianming Zhang, Edward M. Driggers, Sung Choe, Xiaoxu Wang, Jeremy H. Tchaicha, Abigail B. Altabef, Zhao Chen, Yong Zhang, Peng Gao, Travis J. Cohoon, Chunxiao Xu, Thomas J.F. Nieland, Qingsong Liu, Julian Carretero, Glenn S. Cowley, Kevin Marks, and Yan Liu
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Supplementary Figure S1. Generation of GEMM-derived cell lines. Supplementary Figure S2. QPCR and Western blot analyses of DTYMK expression in 634 cells upon indicated shDtymks transduction. Supplementary Figure S3. Lkb1-wt 634 and Lkb1-null t4 cells transduced with shGFP, shDtymk-1 or shDtymk-3 and then cultured with or without additional 100 microM dTTP in medium for 4 days. Supplementary Figure S4. Lkb1-wt (634, 855, and 857) and Lkb1-null (t2, t4, and t5) cell lines (A) and human LKB1-wt (H358 and Calu-1) and LKB1-deficient H2122 and A549) NSCLC cell lines (B) were treated with CHEK1 inhibitors, AZD7762 and CHIR124, for the indicated dose and time, and then lysed for Western blot analysis of gammaH2AX. Supplementary Figure S5. Immunohistochemical analyses assessing gammaH2AZ. Supplementary Figure S6. QPCR and Western blot analyses of DTYMK expression in LKB1-wt Calu-1 NSCLC cells. Supplementary Figure S7. A schematic model is proposed based on our current data. Supplementary Figure S8. QPCR analyses of Dtymk (A) and Chek1 (B) transcript levels in Lkb1-wt (634, 855, and 857) and Lkb1-null (t2, t4, and t5) cell lines. Supplementary Figure S9. QPCR analysis of TK1 expression in 634 cells upon the indicated shTK1 transduction for 3 days. Supplementary Figure S10. Gene expression levels of DTYMK in normal lung vs. lung adenocarcinoma from the Oncomine Cancer Microarray database.
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- 2023
7. Supplementary Table S1.5 from Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in LKB1-Mutant Lung Cancer
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Kwok-Kin Wong, Lewis C. Cantley, David E. Root, Nathanael S. Gray, Andrew L. Kung, William Y. Kim, David J. Kwiatkowski, John V. Heymach, Ignacio I. Wistuba, Don L. Gibbons, Lauren A. Byers, Alec Kimmelman, Ralph Scully, John M. Asara, Reuben J. Shaw, Brendan D. Manning, Jeffrey A. Engelman, Nabeel Bardeesy, Pasi A. Janne, Nirali M. Patel, D. Neil Hayes, Norman E. Sharpless, Sean T. Bailey, Jianming Zhang, Edward M. Driggers, Sung Choe, Xiaoxu Wang, Jeremy H. Tchaicha, Abigail B. Altabef, Zhao Chen, Yong Zhang, Peng Gao, Travis J. Cohoon, Chunxiao Xu, Thomas J.F. Nieland, Qingsong Liu, Julian Carretero, Glenn S. Cowley, Kevin Marks, and Yan Liu
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Validation hits.
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- 2023
8. Supplementary Table S2 from Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in LKB1-Mutant Lung Cancer
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Kwok-Kin Wong, Lewis C. Cantley, David E. Root, Nathanael S. Gray, Andrew L. Kung, William Y. Kim, David J. Kwiatkowski, John V. Heymach, Ignacio I. Wistuba, Don L. Gibbons, Lauren A. Byers, Alec Kimmelman, Ralph Scully, John M. Asara, Reuben J. Shaw, Brendan D. Manning, Jeffrey A. Engelman, Nabeel Bardeesy, Pasi A. Janne, Nirali M. Patel, D. Neil Hayes, Norman E. Sharpless, Sean T. Bailey, Jianming Zhang, Edward M. Driggers, Sung Choe, Xiaoxu Wang, Jeremy H. Tchaicha, Abigail B. Altabef, Zhao Chen, Yong Zhang, Peng Gao, Travis J. Cohoon, Chunxiao Xu, Thomas J.F. Nieland, Qingsong Liu, Julian Carretero, Glenn S. Cowley, Kevin Marks, and Yan Liu
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shRNAs used in manuscript.
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- 2023
9. Discovery of AG-270, a First-in-Class Oral MAT2A Inhibitor for the Treatment of Tumors with Homozygous MTAP Deletion
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Joshua Murtie, Anil K. Padyana, Lei Jin, Marc L. Hyer, Zhixiao Liu, Scott A. Biller, Jeremy Travins, Amelia Barnett, Katya Marjon, Brandon Nicolay, Wentao Wei, Raj Nagaraja, Cheng Fang, Yi Gao, Yabo Sun, Ye Zhixiong, Fan Jiang, Peter Kalev, Stefan Gross, Zenon D. Konteatis, Byron DeLaBarre, Zhihua Sui, Kevin Marks, Lenny Dang, Jie Yu, Everton Mandley, and Yue Chen
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chemistry.chemical_classification ,0303 health sciences ,Methionine ,Allosteric regulation ,01 natural sciences ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Enzyme ,chemistry ,CDKN2A ,Methionine Adenosyltransferase ,Drug Discovery ,Cancer cell ,Cancer research ,Molecular Medicine ,Structure–activity relationship ,Binding site ,030304 developmental biology - Abstract
The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was recently implicated as a synthetic lethal target in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene, which is adjacent to the CDKN2A tumor suppressor and codeleted with CDKN2A in approximately 15% of all cancers. Previous attempts to target MAT2A with small-molecule inhibitors identified cellular adaptations that blunted their efficacy. Here, we report the discovery of highly potent, selective, orally bioavailable MAT2A inhibitors that overcome these challenges. Fragment screening followed by iterative structure-guided design enabled >10 000-fold improvement in potency of a family of allosteric MAT2A inhibitors that are substrate noncompetitive and inhibit release of the product, S-adenosyl methionine (SAM), from the enzyme's active site. We demonstrate that potent MAT2A inhibitors substantially reduce SAM levels in cancer cells and selectively block proliferation of MTAP-null cells both in tissue culture and xenograft tumors. These data supported progressing AG-270 into current clinical studies (ClinicalTrials.gov NCT03435250).
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- 2021
10. Cancer Dependencies: PRMT5 and MAT2A in MTAP/p16-Deleted Cancers
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Peter Kalev, Katya Marjon, and Kevin Marks
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0301 basic medicine ,Cancer Research ,Protein arginine methyltransferase 5 ,Cancer ,Cell Biology ,Biology ,medicine.disease ,law.invention ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,law ,CDKN2A ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Suppressor - Abstract
Discovery of targeted therapies that selectively exploit the genetic inactivation of specific tumor suppressors remains a major challenge. This includes the prevalent deletion of the CDKN2A/ MTAP locus, which was first reported nearly 40 years ago. The more recent advent of RNA interference and functional genomic screening technologies led to the identification of hidden collateral lethalities occurring with passenger deletions of MTAP in cancer cells. In particular, small-molecule inhibition of the type II arginine methyltransferase PRMT5 and the S-adenosylmethionine-producing enzyme MAT2A each presents a precision medicine approach for the treatment of patients whose tumors have homozygous loss of MTAP. In this review, we highlight key aspects of MTAP, PRMT5, and MAT2A biology to provide a conceptual framework for developing novel therapeutic strategies in tumors with MTAP deletion and to summarize ongoing efforts to drug PRMT5 and MAT2A.
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- 2021
11. A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition
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Lingling Huang, Kevin Marks, Shengfang Jin, Sung Choe, Scott A. Biller, Joshua Murtie, Gromoslaw A. Smolen, Janeta Popovici-Muller, Eric L. Allen, Rohini Narayanaswamy, Stefan Gross, Yingjia Zhang, Wei Liu, Thomas P. Roddy, Gabrielle McDonald, Nelamangala Nagaraja, Marion Dorsch, Anil K. Padyana, Christopher E. Mahoney, Taryn Sleger, Meina Liu, Yue Chen, Stuart Murray, Victor Chubukov, Sebastian Hayes, Giovanni Cianchetta, Ying Chen, Zi Peng Fan, and David Pirman
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0301 basic medicine ,Squalene monooxygenase ,Science ,Cell ,Chemical biology ,General Physics and Astronomy ,Antineoplastic Agents ,02 engineering and technology ,Neuroendocrine tumors ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Gene Expression Regulation, Enzymologic ,03 medical and health sciences ,Drug Delivery Systems ,Cell Line, Tumor ,medicine ,Humans ,lcsh:Science ,Regulation of gene expression ,Multidisciplinary ,Cancer ,General Chemistry ,021001 nanoscience & nanotechnology ,medicine.disease ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Cholesterol ,Squalene Monooxygenase ,Cell culture ,Cancer cell ,Cancer research ,lcsh:Q ,Drug Screening Assays, Antitumor ,0210 nano-technology ,Gene Deletion - Abstract
Aberrant metabolism of cancer cells is well appreciated, but the identification of cancer subsets with specific metabolic vulnerabilities remains challenging. We conducted a chemical biology screen and identified a subset of neuroendocrine tumors displaying a striking pattern of sensitivity to inhibition of the cholesterol biosynthetic pathway enzyme squalene epoxidase (SQLE). Using a variety of orthogonal approaches, we demonstrate that sensitivity to SQLE inhibition results not from cholesterol biosynthesis pathway inhibition, but rather surprisingly from the specific and toxic accumulation of the SQLE substrate, squalene. These findings highlight SQLE as a potential therapeutic target in a subset of neuroendocrine tumors, particularly small cell lung cancers., Cancer cells are metabolically adaptable and the identification of specific vulnerabilities is challenging. Here the authors identify a subset of neuroendocrine cell lines exquisitely sensitive to inhibition of SQLE, an enzyme in the cholesterol biosynthetic pathway, due to the toxic accumulation of pathway intermediate squalene.
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- 2019
12. Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase
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K. Satish Reddy, Scott A. Biller, Kavitha Nellore, Siva Sanjeeva Rao, Anil K. Padyana, Georg Lenz, Thomas Antony, Charles Locuson, Jonathan Hurov, Mya Steadman, Tabea Erdmann, Mark Fletcher, Zi Peng Fan, Kevin Truskowski, Sreevalsam Gopinath, Alan Mann, Danielle Ulanet, Rohini Narayanaswamy, Sebastien Ronseaux, Gabrielle McDonald, Sung Choe, Zhihua Sui, John Coco, Lenny Dang, Kevin Marks, Victor Chubukov, Erin Artin, Sebastian Hayes, Josh Murtie, Lei Jin, Nelamangala Nagaraja, Hosahalli Subramanya, and Sunil Kumar Panigrahi
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0301 basic medicine ,Proteomics ,Cancer Research ,Oxidoreductases Acting on CH-CH Group Donors ,Cell Survival ,Chemical biology ,Dihydroorotate Dehydrogenase ,Antineoplastic Agents ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,medicine ,Extracellular ,Humans ,Enzyme Inhibitors ,Neoplasm Staging ,Genomics ,medicine.disease ,Uridine ,Lymphoma ,Metabolic pathway ,030104 developmental biology ,Pyrimidines ,Oncology ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,Hematologic Neoplasms ,Cancer research ,Dihydroorotate dehydrogenase ,DNA Damage - Abstract
Agents targeting metabolic pathways form the backbone of standard oncology treatments, though a better understanding of differential metabolic dependencies could instruct more rationale-based therapeutic approaches. We performed a chemical biology screen that revealed a strong enrichment in sensitivity to a novel dihydroorotate dehydrogenase (DHODH) inhibitor, AG-636, in cancer cell lines of hematologic versus solid tumor origin. Differential AG-636 activity translated to the in vivo setting, with complete tumor regression observed in a lymphoma model. Dissection of the relationship between uridine availability and response to AG-636 revealed a divergent ability of lymphoma and solid tumor cell lines to survive and grow in the setting of depleted extracellular uridine and DHODH inhibition. Metabolic characterization paired with unbiased functional genomic and proteomic screens pointed to adaptive mechanisms to cope with nucleotide stress as contributing to response to AG-636. These findings support targeting of DHODH in lymphoma and other hematologic malignancies and suggest combination strategies aimed at interfering with DNA-damage response pathways.
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- 2020
13. Future Directions of Training and Fieldwork in Diversity Issues in Applied Behavior Analysis
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Ashlynn Johnson, Ranim Murriky, Brian Conners, Jacqueline Duarte, and Kevin Marks
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050103 clinical psychology ,Medical education ,ComputingMilieux_THECOMPUTINGPROFESSION ,media_common.quotation_subject ,medicine.medical_treatment ,05 social sciences ,Context (language use) ,General Medicine ,Certification ,Training (civil) ,Special Section: Diversity and Inclusion ,Multiculturalism ,medicine ,0501 psychology and cognitive sciences ,Culturally competent ,Psychology ,Applied behavior analysis ,050104 developmental & child psychology ,media_common ,Diversity (politics) - Abstract
This paper examines the perceptions of behavior-analytic professionals holding credentials through the Behavior Analyst Certification Board® (BACB®)-including Board Certified Behavior Analysts-Doctoral™, Board Certified Behavior Analysts®, and Board Certified Assistant Behavior Analysts®-regarding multiculturalism and diversity issues in their graduate training, fieldwork, and supervision. This paper predominantly focuses on future directions for improving graduate training, fieldwork, and supervision requirements in the field of applied behavior analysis (ABA) to produce more culturally competent professionals. Results from a preliminary survey of BACB® certificants (N = 575) are included to provide a context for recommendations on how to move the field of ABA forward to enhance the training and preparation of future credentialed professionals.
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- 2020
14. Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML
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Sung Choe, Zenon D. Konteatis, Chris Bowden, Brandon Nicolay, Courtney D. DiNardo, Bin Wu, Jessica K. Altman, Alice S. Mims, Lenny Dang, Scott A. Biller, Guowen Liu, Daniel A. Pollyea, Parham Nejad, Hongfang Wang, Eyal C. Attar, Richard Stone, Stéphane de Botton, Wei Liu, Vickie Zhang, Eytan M. Stein, Kevin Marks, Justin M. Watts, Gail J. Roboz, Meredith Goldwasser, Lynn Quek, Amir T. Fathi, Hua Liu, Hagop M. Kantarjian, and Martin S. Tallman
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0301 basic medicine ,Myeloid ,IDH1 ,Combination therapy ,Pyridines ,Glycine ,IDH2 ,Receptor tyrosine kinase ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,medicine ,Humans ,Myeloid Neoplasia ,biology ,business.industry ,Myeloid leukemia ,Hematology ,medicine.disease ,Isocitrate Dehydrogenase ,Leukemia ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,Isocitrate dehydrogenase ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,business - Abstract
Isocitrate dehydrogenase (IDH) 1 and 2 mutations result in overproduction of D-2-hydroxyglutarate (2-HG) and impaired cellular differentiation. Ivosidenib, a targeted mutant IDH1 (mIDH1) enzyme inhibitor, can restore normal differentiation and results in clinical responses in a subset of patients with mIDH1 relapsed/refractory (R/R) acute myeloid leukemia (AML). We explored mechanisms of ivosidenib resistance in 174 patients with confirmed mIDH1 R/R AML from a phase 1 trial. Receptor tyrosine kinase (RTK) pathway mutations were associated with primary resistance to ivosidenib. Multiple mechanisms contributed to acquired resistance, particularly outgrowth of RTK pathway mutations and 2-HG–restoring mutations (second-site IDH1 mutations, IDH2 mutations). Observation of multiple concurrent mechanisms in individual patients underscores the complex biology of resistance and has important implications for rational combination therapy design. This trial was registered at www.clinicaltrials.gov as #NCT02074839
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- 2020
15. MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage
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Rachel Peters, Kate Lizotte, Victoria Frank, Yesim Tuncay, Katie Sellers, Elia Aguado-Fraile, Marc L. Hyer, Everton Mandley, Scott A. Biller, Michelle Clasquin, Katya Marjon, Phong Quang, Jeremy Travins, Joshua E. Goldford, Zenon D. Konteatis, Chi-Chao Chen, Jaclyn Weier, Lenny Dang, Raj Nagaraja, Peter Kalev, Kevin Marks, Wei Liu, Eric Simone, Joshua Murtie, Stefan Gross, Max Lein, Yue Chen, Mark Fletcher, Amelia Barnett, Zhihua Sui, and Sebastian Hayes
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0301 basic medicine ,Protein-Arginine N-Methyltransferases ,S-Adenosylmethionine ,Cancer Research ,DNA damage ,RNA Splicing ,Mice, Nude ,Mice, SCID ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Mice, Inbred NOD ,CDKN2A ,Cell Line, Tumor ,Neoplasms ,Animals ,Humans ,RNA, Messenger ,Enzyme Inhibitors ,Gene ,Cyclin-Dependent Kinase Inhibitor p16 ,Kinase ,Chemistry ,Protein arginine methyltransferase 5 ,Methionine Adenosyltransferase ,HCT116 Cells ,HEK293 Cells ,030104 developmental biology ,Purine-Nucleoside Phosphorylase ,Oncology ,030220 oncology & carcinogenesis ,RNA splicing ,Cancer cell ,Cancer research ,Gene Deletion ,DNA Damage - Abstract
The methylthioadenosine phosphorylase (MTAP) gene is located adjacent to the cyclin-dependent kinase inhibitor 2A (CDKN2A) tumor-suppressor gene and is co-deleted with CDKN2A in approximately 15% of all cancers. This co-deletion leads to aggressive tumors with poor prognosis that lack effective, molecularly targeted therapies. The metabolic enzyme methionine adenosyltransferase 2α (MAT2A) was identified as a synthetic lethal target in MTAP-deleted cancers. We report the characterization of potent MAT2A inhibitors that substantially reduce levels of S-adenosylmethionine (SAM) and demonstrate antiproliferative activity in MTAP-deleted cancer cells and tumors. Using RNA sequencing and proteomics, we demonstrate that MAT2A inhibition is mechanistically linked to reduced protein arginine methyltransferase 5 (PRMT5) activity and splicing perturbations. We further show that DNA damage and mitotic defects ensue upon MAT2A inhibition in HCT116 MTAP-/- cells, providing a rationale for combining the MAT2A clinical candidate AG-270 with antimitotic taxanes.
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- 2021
16. MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis
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Scott A. Biller, Michelle L. Blake, Joshua Murtie, Everton Mandley, Kevin Marks, Zenon D. Konteatis, Andrew Kernytsky, Michael J. Cameron, Sung Choe, Marion Dorsch, Jeremy Travins, Kaiko Kunii, Stefan Gross, Michelle Clasquin, Katya Marjon, Phong Quang, and Michael McVay
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0301 basic medicine ,Protein-Arginine N-Methyltransferases ,Methyltransferase ,Adenosine ,Purine nucleoside phosphorylase ,Synthetic lethality ,Biology ,Protein Serine-Threonine Kinases ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,CDKN2A ,Antigens, Neoplasm ,Neoplasms ,Humans ,RNA, Small Interfering ,lcsh:QH301-705.5 ,Thionucleosides ,Protein arginine methyltransferase 5 ,Methylation ,Genomics ,Methionine Adenosyltransferase ,HCT116 Cells ,Molecular biology ,030104 developmental biology ,Purine-Nucleoside Phosphorylase ,lcsh:Biology (General) ,Multiprotein Complexes ,Gene Deletion ,Signal Transduction - Abstract
SummaryHomozygous deletions of p16/CDKN2A are prevalent in cancer, and these mutations commonly involve co-deletion of adjacent genes, including methylthioadenosine phosphorylase (MTAP). Here, we used shRNA screening and identified the metabolic enzyme, methionine adenosyltransferase II alpha (MAT2A), and the arginine methyltransferase, PRMT5, as vulnerable enzymes in cells with MTAP deletion. Metabolomic and biochemical studies revealed a mechanistic basis for this synthetic lethality. The MTAP substrate methylthioadenosine (MTA) accumulates upon MTAP loss. Biochemical profiling of a methyltransferase enzyme panel revealed that MTA is a potent and selective inhibitor of PRMT5. MTAP-deleted cells have reduced PRMT5 methylation activity and increased sensitivity to PRMT5 depletion. MAT2A produces the PRMT5 substrate S-adenosylmethionine (SAM), and MAT2A depletion reduces growth and PRMT5 methylation activity selectively in MTAP-deleted cells. Furthermore, this vulnerability extends to PRMT5 co-complex proteins such as RIOK1. Thus, the unique biochemical features of PRMT5 create an axis of targets vulnerable in CDKN2A/MTAP-deleted cancers.
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- 2016
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17. Abstract 3090: The MAT2A inhibitor, AG-270, combines with both taxanes and gemcitabine to yield enhanced anti-tumor activity in patient-derived xenograft models
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Elia Aguado-Fraile, Sheila Newhouse, Mark Fletcher, Chi-Chao Chen, Marc L. Hyer, Katya Marjon, Raj Nagaraja, Max Lein, Yesim Tuncay, Josh Murtie, Everton Mandley, Kevin Marks, and Peter Kalev
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0301 basic medicine ,Cancer Research ,DNA damage ,business.industry ,Cell ,Phases of clinical research ,Gemcitabine ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,Mechanism of action ,Paclitaxel ,chemistry ,Docetaxel ,In vivo ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,medicine.symptom ,business ,medicine.drug - Abstract
MAT2A (methionine adenosyltransferase 2 alpha) is a critical enzyme within the methionine salvage pathway responsible for generating the universal methyl group donor, S-adenosyl methionine (SAM). We have developed a first-in-class small molecule inhibitor of MAT2A, AG-270, currently in a phase 1 clinical study (ClinicalTrials.gov NCT03435250) for the treatment of patients with solid tumors or lymphomas with MTAP (methylthioadenosine phosphorylase) deletion. The MTAP gene is deleted in approximately 15% of all human cancers, including non-small cell lung cancer (NSCLC; ~15-25%), pancreatic (~25%) and esophageal (~30%) cancer, and glioblastoma (~50%). To prioritize candidate combination partners for AG-270, a cell-based in vitro screening approach was employed using MTAP-null cell lines, in which AG-270 was combined with standard-of-care (SOC) agents as well as agents targeting pathways with hypothesized mechanistic links to MAT2A. Some of the best performing enhancers from this screen included paclitaxel (and docetaxel, using orthogonal screens) and gemcitabine. To assess the robustness of these combination findings in clinically relevant in vivo models, a series of patient-derived xenograft (PDX) experiments was undertaken to evaluate tolerability and efficacy in mice. Results demonstrated that AG-270, when combined with taxanes (paclitaxel/docetaxel) or gemcitabine, was well tolerated using SOC plasma exposures less than or equal to those achieved in patients. Importantly, combining AG-270 with taxanes and gemcitabine yielded additive-to-synergistic anti-tumor activity, with the docetaxel combination yielding 50% complete tumor regressions (CRs) in 2-3 PDX models. To study the mechanism of action, MAT2A was inhibited in vitro within HCT-116 MTAP −/− and wild-type cells, and we observed RNA splicing changes (via detained introns) altering genes involved in cell cycle regulation and DNA damage response, with a more pronounced effect found in the MTAP −/− genetic setting. Moreover, detained introns involving these same two pathways were modulated in MTAP −/− NSCLC PDX models treated with AG-270. Taken together, these data suggest AG-270 complements the known mechanism of action of taxanes and gemcitabine, and leads to enhanced DNA damage and inhibition of cellular proliferation. This work has helped identify a therapeutic strategy of combining AG-270 with taxanes and gemcitabine, which is currently being explored in an ongoing phase 1 clinical trial (NCT03435250). Page 1 of 1 Citation Format: Marc L. Hyer, Peter Kalev, Mark Fletcher, Chi-Chao Chen, Elia Aguado-Fraile, Everton Mandley, Sheila Newhouse, Max Lein, Raj Nagaraja, Yesim Tuncay, Josh Murtie, Kevin M. Marks, Katya Marjon. The MAT2A inhibitor, AG-270, combines with both taxanes and gemcitabine to yield enhanced anti-tumor activity in patient-derived xenograft models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3090.
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- 2020
18. Abstract B115: Mitotic defects induced by MAT2A inhibitors guides translational drug combination strategies with AG-270 and taxanes
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Kevin Marks, Peili Zhang, Katya Marjon, Zenon D. Konteatis, Yesim Tuncay, Mark Fletcher, Marc L. Hyer, Everton Mandley, Jeremy Travins, Peter Kalev, and Elia Aguado-Fraile
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Cancer Research ,Methyltransferase ,DNA damage ,Chemistry ,Protein arginine methyltransferase 5 ,Cell ,Cancer ,medicine.disease ,medicine.anatomical_structure ,Oncology ,Cell culture ,Cancer cell ,Cancer research ,medicine ,Mitosis - Abstract
Methylthioadenosine phosphorylase (MTAP) is the enzyme in the methionine salvage pathway that metabolizes the byproduct of polyamine biosynthesis, 5′-methylthioadenosine (MTA). The MTAP gene is deleted in approximately 15% of all human cancers and results in accumulation of MTA that partially inhibits protein arginine methyl transferase 5 (PRMT5) function. Recent studies have demonstrated that loss of the MTAP gene sensitizes cancer cells to genetic depletion of PRMT5 and the upstream metabolic enzyme methionine adenosyltransferase 2 alpha (MAT2A). We have developed a first-in-class, highly potent, orally bioavailable MAT2A inhibitor, AG-270, which is currently under investigation in a phase 1 clinical trial (ClinicalTrials.gov NCT03435250). AG-270 selectively inhibits the growth of HCT116 MTAP-/- cells compared to HCT116 MTAP+/+ cells in vitro and in vivo. We utilized RNA sequencing and proteomic approaches to study the underlying mechanism of action for AG-270. The results of these analyses demonstrated that AG-270 treatment induces substantial splicing changes in an MTAP selective manner. The majority of these abnormal splicing events were detained introns, which included genes involved in cell cycle regulation and DNA damage response. Moreover, AG-270 treatment resulted in accumulation of DNA damage and increased mitotic defects in HCT116 MTAP-/- cells. Furthermore, we demonstrated substantially advantageous combination benefits between AG-270 and anti-mitotic taxanes in in vitro cell lines and in in vivo patient-derived xenograft models of non-small cell lung, pancreatic and esophageal cancers. These findings uncover relevant combination strategies targeting MTAP-deleted malignancies, and provide preclinical mechanistic proof-of-concept to explore such combinations in the clinical setting. Citation Format: Peter Kalev, Marc L Hyer, Mark Fletcher, Peili Zhang, Elia Aguado-Fraile, Everton Mandley, Yesim Tuncay, Zenon Konteatis, Jeremy Travins, Kevin M Marks, Katya Marjon. Mitotic defects induced by MAT2A inhibitors guides translational drug combination strategies with AG-270 and taxanes [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B115. doi:10.1158/1535-7163.TARG-19-B115
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- 2019
19. Abstract PR03: A phase 1 trial of AG-270 in patients with advanced solid tumors or lymphoma with homozygous MTAP deletion
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Kevin Marks, Patricia Martin-Romano, Geoffrey I. Shapiro, Howard A. Burris, Rebecca S. Heist, Sophie Postel-Vinay, Keith T. Flaherty, Michael Cooper, Elena Garralda, Frederick Wilson, Khanh T. Do, Yanwei Zhang, Elia Aguado-Fraile, Varsha Iyer, Caroline Almon, Frank G. Basile, Salah Nabhan, Gerburg M. Wulf, and Mrinal M. Gounder
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Taxane ,business.industry ,medicine.medical_treatment ,Area under the curve ,Cancer ,medicine.disease ,Gastroenterology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Pharmacokinetics ,Tolerability ,CDKN2A ,030220 oncology & carcinogenesis ,Internal medicine ,Pharmacodynamics ,medicine ,business - Abstract
Background: Homozygous deletion of MTAP, the gene encoding the metabolic enzyme methylthioadenosine phosphorylase, occurs in ~15% of human malignancies. Tumor cells with this deletion are selectively vulnerable to decreases in the methyl donor S-adenosylmethionine (SAM). AG-270 is a first-in-class, oral, potent, reversible inhibitor of methionine adenosyltransferase 2A (MAT2A), the key enzyme responsible for SAM synthesis. We report preliminary results from an ongoing, first-in-human, phase 1 trial of AG-270 (ClinicalTrials.gov Identifier: NCT03435250). Aims: The primary objective of this study is to determine the maximum tolerated dose (MTD) of AG-270. Secondary objectives include safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Methods: Eligibility requires homozygous deletion of cyclin dependent kinase inhibitor 2A (CDKN2A) in the patient’s tumor (as MTAP is usually co-deleted with CDKN2A), or loss of MTAP by IHC. Patients receive AG-270 daily in 28-day cycles, with intensive PK/PD sampling after the first dose and after 2 weeks of treatment. Paired tumor biopsies are collected at baseline and at the end of cycle 1. Disease evaluation is performed every 2 cycles. Results: As of 20 May 2019, 39 patients had been treated with AG-270: 50 mg once daily (QD; n=3), 100 mg QD (n=7), 150 mg QD (n=6), 200 mg QD (n=11), 400 mg QD (n=6), or 200 mg twice daily (BID; n=6). AG-270 was well absorbed. Plasma concentrations increased in a dose-proportional manner except at 400 mg QD, where exposure was lower than anticipated. The geometric mean area under the curve from 0-24 h at steady state (AUC0-24,ss) in the QD cohorts ranged from 33200 to 199085 ng*h/mL, and the geometric mean AUC0-24,ss in the 200 mg BID cohort was 254616 ng*h/mL. The median half-life of AG-270 ranged from 16.1 to 38.4 h. Decreases in plasma [SAM] were exposure-dependent. After 2 weeks of dosing, maximal reductions in plasma [SAM] ranged from 51% to 71% across the tested cohorts. Analysis of 9 paired tumor biopsies by IHC showed decreases in levels of symmetrically di-methylated arginine (SDMA) residues, consistent with MAT2A inhibition; the average H-score reduction compared to baseline was 36.4% [-98.8%, +21.4%]. Asymptomatic, exposure-dependent increases in unconjugated bilirubin were observed starting at 100 mg QD, consistent with the known potential of AG-270 to inhibit UGT1A1. Three patients (at 100 mg QD, 150 mg QD, and 200 mg BID) developed grade 2 and 3 diffuse erythematous rashes during the second week of dosing that resolved within 1 week of stopping treatment. Exposure-dependent, reversible decreases in platelet counts were first observed at 200 mg QD and were grade 3 and 4 in severity at 200 mg BID. Two patients treated at 200 mg BID developed reversible but dose-limiting grade 3 and 4 increases in liver enzymes. The MTD of AG-270 is 200 mg QD. An unconfirmed partial response has been observed in a patient with a high-grade neuroendocrine carcinoma of the lung. Seven patients have achieved radiographically confirmed stable disease of 2.0 to 9.9 months’ duration. Conclusions: AG-270 causes reductions in plasma [SAM] and in tumor SDMA levels at well-tolerated doses. This trial will next evaluate the combination of AG-270 with taxane-based chemotherapy, given preclinical data demonstrating enhanced antitumor activity with AG-270 and taxanes in MTAP-deleted cancer models. Citation Format: Rebecca S Heist, Mrinal M Gounder, Sophie Postel-Vinay, Frederick Wilson, Elena Garralda, Khanh Do, Geoffrey I Shapiro, Patricia Martin-Romano, Gerburg Wulf, Michael Cooper, Caroline Almon, Salah Nabhan, Varsha Iyer, Yanwei Zhang, Kevin Marks, Elia Aguado-Fraile, Frank Basile, Keith Flaherty, Howard A Burris. A phase 1 trial of AG-270 in patients with advanced solid tumors or lymphoma with homozygous MTAP deletion [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PR03. doi:10.1158/1535-7163.TARG-19-PR03
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- 2019
20. Corrigendum: mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer
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Ruzica Bago, Naiara Beraza, Alfredo Caro-Maldonado, Ana Loizaga-Iriarte, Natalia Martín-Martín, Arkaitz Carracedo, Elena Castro, Violeta Serra, Mikel Azkargorta, Diana Cabrera, Michelle Clasquin, Katya Marjon, Phong Quang, Kevin Marks, Inés de Torres, Rosa Farràs, Marco Piva, Ana R. Cortazar, Ludmila Prudkin, Sonia Fernández-Ruiz, José Baselga, Julen Tomás-Cortázar, Josep Tabernero, Amelia Barnett, Sebastiaan M. Van Liempd, Carlos Cordon-Cardo, Miguel Unda, Ianire Astobiza, Rosa Barrio, Juan M. Falcón-Pérez, David Olmos, Javier Munoz, Ajinkya Revandkar, Patricia Zúñiga-García, José Antonio Jiménez, Brendan D. Manning, James D. Sutherland, Mireia Castillo-Martin, Ana M. Aransay, Pilar Sanchez-Mosquera, Leire Arreal, Alejo Efeyan, Antonio Gentilella, Itziar Fernández-Domínguez, Felix Elortza, Paolo Nuciforo, Amaia Zabala-Letona, Amaia Arruabarrena-Aristorena, David Pirman, Isabel Lacasa-Viscasillas, Juan Anguita, Gina Lein, Ylenia Cendon, Stuart Murray, Pilar Ximénez-Embún, Andrea Alimonti, Lorea Valcarcel-Jimenez, Verónica Torrano, George Thomas, Aitziber Ugalde-Olano, Teresa Macarulla, María L. Martínez-Chantar, José M. Mato, and Yinan Zhang
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Multidisciplinary ,Published Erratum ,Biology ,medicine.disease ,03 medical and health sciences ,Prostate cancer ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Polyamine metabolism - Abstract
Nature 547, 109–113 (2017); doi:10.1038/nature22964 In this Letter, there are errors in Extended Data Figs 5, 8 and 9, and the affiliation of an author. The affiliations for author Violeta Serra should include number 2 (CIBERONC, Instituto de Salud Carlos III, C/ Monforte de Lemos 3-5, Pabellon 11, Planta 0, 28029 Madrid, Spain).
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- 2018
21. Abstract 2714: Targeting MAT2A in CDKN2A/MTAP-deleted cancers
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Zenon D. Konteatis, Peili Zhang, Katya Marjon, Peter Kalev, Marc L. Hyer, Mark Fletcher, Elia Aguado-Fraile, Jeremy Travins, Everton Mandley, and Kevin Marks
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Cancer Research ,DNA damage ,DNA repair ,Protein arginine methyltransferase 5 ,Cancer ,Methylation ,Biology ,medicine.disease ,chemistry.chemical_compound ,Oncology ,chemistry ,CDKN2A ,Cancer cell ,Cancer research ,medicine ,Growth inhibition - Abstract
While deletions of the p16/CDKN2A tumor suppressor were first discovered more than 30 years ago, therapeutics that selectively target such tumors have proven elusive. Recent work utilizing functional genomics has identified a synthetic lethal vulnerability that arises due to co-deletion of the adjacent metabolic gene, methylthioadenosine phosphorylase (MTAP). Loss of MTAP in these tumors leads to an accumulation of MTAP substrate 5'-methylthioadenosine (MTA), which partially inhibits the arginine methyltransferase PRMT5 and sensitizes tumors to shRNA-mediated depletion of PRMT5 and the upstream metabolic enzyme, methionine adenosyltransferase 2 alpha (MAT2A). To investigate the therapeutic potential of this finding, we utilized a biophysical binding screen followed by iterative structure-guided design to make the first highly potent, selective, and orally bioavailable inhibitors of MAT2A. MAT2A inhibitor treatment leads to potent inhibition of the growth of HCT116 MTAP-/- cells while sparing isogenic HCT116 MTAP+/+ cells. Tumor xenograft studies similarly demonstrated MTAP-selective growth inhibition in HCT116 MTAP-/- tumors compared to isogenic HCT116 MTAP+/+ tumors. Further, MTAP-deletion correlated with MAT2A inhibitor efficacy across a panel of >300 cell lines in vitro, and MAT2A inhibitor treatment was efficacious in a variety of MTAP-deleted patient-derived xenografts in vivo. Having demonstrated that potent MAT2A inhibitors selectively block the proliferation of MTAP-deleted cells and tumors, we sought to investigate the mechanism by which these effects arise. Using methylation proteomics we noted that MAT2A inhibitor treatment leads to selective inhibition of PRMT5 methylation activity in MTAP-deleted cancers in vitro and in vivo. RNA-seq analyses revealed that MAT2A inhibition leads to substantial defects in RNA splicing in MTAP-deleted cancers, consistent with published findings that PRMT5-mediated methylation of splicing complex proteins is critical for their function. MAT2A inhibitor treatment led to a substantial increase in detained introns, which were enriched in genes involved in cell cycle regulation and DNA damage response, thus implicating dysregulated splicing in the antiproliferative effects of MAT2A inhibition in MTAP-deleted cancer cells. Furthermore, we demonstrated substantial drug-drug synergy between MAT2A inhibitors and select agents inhibiting cell cycle progression or DNA repair. Importantly we validated key combination findings in vivo, including demonstration of synergy with the MAT2A inhibitor AG-270 and anti-mitotic taxanes. AG-270 is the first MAT2A inhibitor to enter clinical development and is under investigation in a Phase I trial that is currently enrolling patients with MTAP-deleted solid tumors (NCT03435250). Our findings suggest clinically-applicable combination strategies which may further enhance the efficacy of AG-270 in malignancies with this genetic lesion. Citation Format: Katya Marjon, Peter Kalev, Marc Hyer, Mark Fletcher, Peili Zhang, Elia Aguado-Fraile, Everton Mandley, Zenon Konteatis, Jeremy Travins, Kevin Marks. Targeting MAT2A in CDKN2A/MTAP-deleted cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2714.
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- 2019
22. Small Molecule Activation of PKM2 in Cancer Cells Induces Serine Auxotrophy
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Shinsan M. Su, Shunqi Yan, Ed Driggers, Wentao Wei, Cheng Fang, Shengfang Jin, Jeff Hixon, Yi Gao, Giovanni Cianchetta, Francesco G. Salituro, Lewis C. Cantley, Kevin Qian, Fan Jiang, Sung Choe, Kaiko Kunii, Matthew G. Vander Heiden, Shalini Sethumadhavan, Erin Murphy, Katharine E. Yen, Stuart Murray, Hin Koon Woo, Charles Kung, Jeffrey O. Saunders, Shaohui Wang, Xiling Wang, Wei Liu, Lenny Dang, Kevin Marks, Byron DeLaBarre, Stefan Gross, and Hua Yang
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Models, Molecular ,Thyroid Hormones ,Auxotrophy ,Allosteric regulation ,Clinical Biochemistry ,Biology ,PKM2 ,Biochemistry ,Serine ,Small Molecule Libraries ,Structure-Activity Relationship ,Drug Discovery ,Tumor Cells, Cultured ,Humans ,Glycolysis ,Molecular Biology ,Cell Proliferation ,chemistry.chemical_classification ,Pharmacology ,Dose-Response Relationship, Drug ,Molecular Structure ,Membrane Proteins ,General Medicine ,Cell biology ,Amino acid ,chemistry ,Anaerobic glycolysis ,Cancer cell ,Molecular Medicine ,Carrier Proteins ,Allosteric Site - Abstract
SummaryProliferating tumor cells use aerobic glycolysis to support their high metabolic demands. Paradoxically, increased glycolysis is often accompanied by expression of the lower activity PKM2 isoform, effectively constraining lower glycolysis. Here, we report the discovery of PKM2 activators with a unique allosteric binding mode. Characterization of how these compounds impact cancer cells revealed an unanticipated link between glucose and amino acid metabolism. PKM2 activation resulted in a metabolic rewiring of cancer cells manifested by a profound dependency on the nonessential amino acid serine for continued cell proliferation. Induction of serine auxotrophy by PKM2 activation was accompanied by reduced carbon flow into the serine biosynthetic pathway and increased expression of high affinity serine transporters. These data support the hypothesis that PKM2 expression confers metabolic flexibility to cancer cells that allows adaptation to nutrient stress.
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- 2012
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23. Abstract IA25: Targeting cancers with deletion of the p16/p14 tumor suppressor locus
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Kevin Marks
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Cancer Research ,Methyltransferase ,Kinase ,Protein arginine methyltransferase 5 ,medicine.medical_treatment ,Methylation ,Synthetic lethality ,Biology ,Targeted therapy ,law.invention ,Oncology ,CDKN2A ,law ,Cancer research ,medicine ,Suppressor - Abstract
Mutations in tumor suppressor genes are a hallmark of cancer and contribute substantially to the molecular pathogenesis of the disease. Particularly prevalent are homozygous deletions of the CDKN2A tumor suppressor locus on chromosome 9p21, which occur in at least 15% of all cancer and lead to loss of the dual tumor suppressors p16(INK4A) and p14(ARF). Targeted therapies selective for loss of CDKN2A have proven elusive, and it may be necessary to identify alternate approaches to target tumors with this deletion. Notably, Chr9p21 deletions frequently involve co-deletion of genes proximal to CDKN2A. Foremost among these is the methylthioadenosine phosphorylase (MTAP) gene, which resides within 100 kb of CDKN2A, and is co-deleted in 80-90% of tumors with CDKN2A deletion. We sought therefore to evaluate whether the frequent co-deletion of the adjacent metabolic gene methylthioadenosine phosphorylase (MTAP) creates targetable vulnerabilities. We conducted an shRNA screen in isogenic cells that varied only in their MTAP-deletion status, and identified the metabolic enzyme, methionine adenosyltransferase II, alpha (MAT2A), and the arginine methyltransferase, PRMT5, as vulnerable enzymes in cells with MTAP deletion. Metabolomic and biochemical studies revealed a mechanistic basis for this synthetic lethality. MTAP substrate methylthioadenosine (MTA) accumulates upon MTAP loss, and biochemical profiling of a methyltransferase enzyme panel revealed that MTA is a potent and selective inhibitor of PRMT5. MTAP-deletion leads to reduced basal PRMT5 methylation activity and increased sensitivity to PRMT5 targeting. MAT2A produces PRMT5 substrate S-adenosylmethionine (SAM), and targeting of MAT2A reduces growth and PRMT5 methylation activity selectively in MTAP-deleted cells. Further, this vulnerability extends to PRMT5 co-complex proteins such as the atypical kinase Rio Kinase 1 (RIOK1). Thus, MAT2A, PRMT5, and RIOK1 comprise an unappreciated axis of targets that is selectively vulnerable in CDKN2A/MTAP-deleted tumors. Unique biochemical features of PRMT5 create this vulnerability, which presents a promising new avenue for targeted therapy. Citation Format: Kevin Marks. Targeting cancers with deletion of the p16/p14 tumor suppressor locus. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA25.
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- 2017
24. Metabolic Adaptation in Reprogrammed Cancer Cells
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Charles Kung and Kevin Marks
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chemistry.chemical_classification ,Cell signaling ,Computational biology ,Synthetic lethality ,Biology ,medicine.disease_cause ,Enzyme ,Isocitrate dehydrogenase ,chemistry ,Cancer cell ,medicine ,Epigenetics ,Carcinogenesis ,Tyrosine kinase - Abstract
Cancer metabolism is an emerging field that offers promise in revealing new targets and strategies to treat tumors. Here, we describe several of the major advances in the understanding of how cancer cells rewire their metabolic circuitry and how these insights might be used to develop new drugs. We contrast how gain-of-function mutations in tyrosine kinases and metabolic enzymes such as isocitrate dehydrogenase promote tumorigenesis. While such recurrent mutations have not been described for the vast majority of metabolic enzymes, these enzymes are still potential targets in their own right, or are used by cancer cells in ways that can expose other vulnerabilities. We illustrate how the ability to study metabolism in molecular detail through sophisticated nutrient labeling studies has allowed connections to be made between cancer metabolism and cell signaling, epigenetics, as well as pathways targeted by standard-of-care chemotherapeutics.
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- 2014
25. Transformation-Defective Polyoma Middle T Antigen Mutants Defective in PLCγ, PI-3, or src Kinase Activation Enhance ERK2 Activation and Promote Retinoic Acid-Induced, Cell Differentiation Like Wild-Type Middle T
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Brian Schaffhausen, Van Cherington, Andrew Yen, Susi Varvayanis, and Kevin Marks
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Receptors, Retinoic Acid ,Cellular differentiation ,Retinoic acid ,Down-Regulation ,HL-60 Cells ,Tretinoin ,Retinoic acid receptor beta ,Transfection ,Retinoic acid-inducible orphan G protein-coupled receptor ,Phosphatidylinositol 3-Kinases ,chemistry.chemical_compound ,Humans ,Antigens, Viral, Tumor ,Mitogen-Activated Protein Kinase 1 ,biology ,Phospholipase C gamma ,Cell Cycle ,Cell Differentiation ,Cell Biology ,Retinoic acid receptor gamma ,Cell biology ,Enzyme Activation ,Isoenzymes ,Retinoic acid receptor ,Cell Transformation, Neoplastic ,Retinoid X Receptors ,src-Family Kinases ,Biochemistry ,chemistry ,Retinoic acid receptor alpha ,Type C Phospholipases ,Calcium-Calmodulin-Dependent Protein Kinases ,Mutation ,biology.protein ,Polyomavirus ,Platelet-derived growth factor receptor ,Signal Transduction ,Transcription Factors - Abstract
In HL-60 human myeloblastic leukemia cells, retinoic acid is known to cause cFMS, RAF, MEK, and ERK2 dependent myeloid cell differentiation and G0 arrest associated with RB tumor suppressor protein hypophosphorylation, implicating receptor tyrosine kinase signal transduction in propelling these retinoic acid-induced cellular effects. Furthermore, ectopic expression of polyoma middle T antigen, which activates similar early signal transduction molecules as PDGF class receptors such as cFMS, accelerates these retinoic acid-induced effects. To determine if this depends on middle T's ability to activate PLCgamma, PI-3 kinase, and src-like kinases, stable transfectants of HL-60 cells expressing either the polyoma middle T dl23 mutant, which is defective for PLCgamma and PI-3 kinase activation, or the Delta205 mutant, which in addition has greatly attenuated src-like kinase activation ability, were created and compared to wild-type middle T-transfected HL-60. The transgenes were under control of the retinoic acid (or 1, 25-dihydroxy vitamin D3) inducible Moloney murine leukemia virus LTRs. Expression of the dl23 or Delta205 mutant accelerated retinoic acid-induced cell differentiation. The effects of the mutants were comparable to those of the wild-type middle T. Likewise, retinoic acid-induced G0 arrest of mutant transfected cells and wild-type middle T transfected cells was similar. The same was true for 1, 25-dihydroxy vitamin D3-induced monocytic differentiation as for retinoic acid-induced myeloid differentiation. The mutants did not cause the same slight shortening of the cell cycle as wild-type middle T. Both the mutants and the wild-type middle T caused a similar increase in the cellular basal level of activated ERK2 MAPK. Since retinoic acid increases ERK2 activation, which is necessary for differentiation, the data suggest that mutant and wild-type middle T enhanced the retinoic acid effects by increasing basal levels of ERK2 activation. Consistent with this, the polyoma-induced foreshortening of the time for differentiation coincided with the time for retinoic acid to significantly increase ERK2 activation. As in wild-type HL-60, retinoic acid induced the early down-regulation of RXRalpha in mutant transfectants similar to wild-type middle T transfectants, consistent with no loss or gain of relevant functions due to the mutations. In contrast, vitamin D3 did not down-regulate RXRalpha in HL-60 or transfectants. Polyoma middle T and these transformation-defective mutants thus enhanced ERK2 activation to have an early effect in promoting retinoic acid-induced differentiation without a strong dependence on activating PLCgamma, PI-3 kinase, or src-like kinase.
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- 1999
26. Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a target in LKB1 Mutant Lung Cancer
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Zhao Chen, Kevin Marks, Qingsong Liu, William Y. Kim, Lewis C. Cantley, John V. Heymach, Nathanael S. Gray, Jeffrey A. Engelman, John M. Asara, Norman E. Sharpless, Ignacio I. Wistuba, Lauren Averett Byers, Edward M. Driggers, Ralph Scully, Abigail Altabef, Nirali M. Patel, Peng Gao, Brendan D. Manning, Don L. Gibbons, Yan Liu, Travis J. Cohoon, D. Neil Hayes, Sung Choe, Julian Carretero, Andrew L. Kung, Thomas J.F. Nieland, Jianming Zhang, Sean T. Bailey, Reuben J. Shaw, Alec C. Kimmelman, Xiaoxu Wang, David E. Root, David J. Kwiatkowski, Jeremy H. Tchaicha, Pasi A. Jänne, Glenn S. Cowley, Yong Zhang, Chunxiao Xu, Nabeel Bardeesy, and Kwok-Kin Wong
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DNA Replication ,congenital, hereditary, and neonatal diseases and abnormalities ,Lung Neoplasms ,Mutant ,STK11 ,Biology ,AMP-Activated Protein Kinases ,Protein Serine-Threonine Kinases ,medicine.disease_cause ,Article ,Proto-Oncogene Proteins p21(ras) ,Mice ,Deoxythymidylate kinase ,AMP-Activated Protein Kinase Kinases ,RNA interference ,Cell Line, Tumor ,Carcinoma, Non-Small-Cell Lung ,medicine ,Metabolomics ,Thymine Nucleotides ,Animals ,Humans ,Molecular Targeted Therapy ,Lung cancer ,skin and connective tissue diseases ,Cell Death ,Models, Genetic ,Kinase ,Cell growth ,Genomics ,medicine.disease ,Molecular biology ,High-Throughput Screening Assays ,Oncology ,Gene Knockdown Techniques ,Cancer research ,RNA Interference ,KRAS ,Nucleoside-Phosphate Kinase ,DNA Damage - Abstract
The LKB1/STK11 tumor suppressor encodes a serine/threonine kinase, which coordinates cell growth, polarity, motility, and metabolism. In non–small cell lung carcinoma, LKB1 is somatically inactivated in 25% to 30% of cases, often concurrently with activating KRAS mutations. Here, we used an integrative approach to define novel therapeutic targets in KRAS-driven LKB1-mutant lung cancers. High-throughput RNA interference screens in lung cancer cell lines from genetically engineered mouse models driven by activated KRAS with or without coincident Lkb1 deletion led to the identification of Dtymk, encoding deoxythymidylate kinase (DTYMK), which catalyzes dTTP biosynthesis, as synthetically lethal with Lkb1 deficiency in mouse and human lung cancer lines. Global metabolite profiling showed that Lkb1-null cells had a striking decrease in multiple nucleotide metabolites as compared with the Lkb1–wild-type cells. Thus, LKB1-mutant lung cancers have deficits in nucleotide metabolism that confer hypersensitivity to DTYMK inhibition, suggesting that DTYMK is a potential therapeutic target in this aggressive subset of tumors. Significance: Using cell lines derived from the lung cancers occurring in genetically engineered mice, we conducted an integrative genome-wide short hairpin RNA and metabolite screen to identify DTYMK as a potential therapeutic target in Kras/Lkb1–mutant lung cancer. We believe that DTYMK is tractable for the development of novel therapeutics, and show an integrative approach to target identification that reduces false-positive candidates and should have broad applicability for the development of targeted therapeutics. Cancer Discov; 3(8); 870–9. ©2013 AACR. See related commentary by Marcus and Khuri, p. 843 This article is highlighted in the In This Issue feature, p. 826
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- 2013
27. Abstract LB-307: MTAP deletions in cancer create vulnerability to a MAT2A/PRMT5/RIOK1 axis
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Kevin Marks
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Cancer Research ,Methyltransferase ,Kinase ,Protein arginine methyltransferase 5 ,Synthetic lethality ,Methylation ,Biology ,Molecular biology ,Small hairpin RNA ,chemistry.chemical_compound ,Oncology ,chemistry ,CDKN2A ,Growth inhibition - Abstract
Homozygous deletions of the CDKN2A tumor suppressor locus occur in approximately 15% of all cancer and represent a substantial therapeutic need(1). Targeted therapies selective for loss of CDKN2A have proven elusive, so we sought to evaluate whether the frequent co-deletion of the adjacent metabolic gene methylthioadenosine phosphorylase (MTAP) leads to collateral vulnerabilities. We conducted an shRNA screen in isogenic cells that vary only in their MTAP-deletion status, and identified an axis of targets that become vulnerable upon MTAP loss. Central in this axis is the arginine methyltransferase, PRMT5. Targeting PRMT5 with doxycycline-inducible shRNA impaired the growth of MTAP-deleted HCT116 colon carcinoma cells without impact on the growth of MTAP-wt HCT116 cells. Having identified this synthetic lethality between PRMT5 and MTAP, we sought next to elucidate the mechanistic basis for this relationship. Untargeted metabolomics revealed that MTA, the substrate of the MTAP enzyme reaction, accumulates dramatically in MTAP-deleted cancers. Biochemical profiling across the methyltransferase enzyme family revealed that MTA is a potent and selective inhibitor of PRMT5. Consistent with this in vitro finding, MTA accumulation in MTAP-deleted cancers led to reduced basal PRMT5 methylation. This selective vulnerability extends beyond PRMT5 to methionine adenosyltransferase 2, a (MAT2A), the metabolic enzyme upstream of PRMT5. MAT2A was the top hit in the shRNA screen, and targeting of MAT2A with inducible shRNA led to selective inhibition of growth in MTAP-deleted HCT116 cells in vitro and in vivo. Targeting of MAT2A led to substantial reduction of PRMT5 methylation activity in MTAP-deleted cells, indicating that PRMT5 activity is controlled by levels of substrate SAM and inhibitory metabolite MTA. To assess the therapeutic relevance of this axis in settings with endogenous deletion of the CDKN2A/MTAP locus, we depleted MAT2A in a panel of cancer cell lines and observed selective growth inhibition in the lines with endogenous deletion of CDKN2A/MTAP. Lastly, we noted that RIO Kinase 1 (RIOK1), a PRMT5-interacting protein(2), also scored in the shRNA screen. Doxycycline-inducible shRNA studies validated RIOK1 as an MTAP-selective target, and additional siRNA studies indicated that multiple PRMT5 co-complex members are selectively essential in MTAP-deleted cells. Thus, PRMT5 is the central node in an axis of targets that could be exploited therapeutically in cancers with deletion of CDKN2A/MTAP. References: 1 Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899-905, doi:10.1038/nature08822 (2010). 2 Guderian, G. et al. RioK1, a new interactor of protein arginine methyltransferase 5 (PRMT5), competes with pICln for binding and modulates PRMT5 complex composition and substrate specificity. J. Biol. Chem. 286, 1976-1986, doi:10.1074/jbc.M110.148486 (2011). Citation Format: Kevin Marks. MTAP deletions in cancer create vulnerability to a MAT2A/PRMT5/RIOK1 axis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-307.
- Published
- 2016
28. Functional genomics reveals serine synthesis is essential in PHGDH-amplified breast cancer
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Michael E. Pacold, Shalini Sethumadhavan, Bingbing Yuan, Yoav D. Shaul, Elena F. Brachtel, Jordi Barretina, Mari Mino-Kenudson, Richard Possemato, David M. Sabatini, Hin-Koon Woo, Kıvanç Birsoy, Nicolas Stransky, Albert M. Chan, Dohoon Kim, Nada Y. Kalaany, Zhi-Yang Tsun, Levi A. Garraway, Glenn S. Cowley, David E. Root, Abhishek K. Jha, Francesca G. Barrett, Edward M. Driggers, Kevin Marks, Hyun Gyung Jang, Walter W. Chen, Kathleen Ottina, Peggy P. Hsu, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research at MIT, Possemato, Richard, Shaul, Yoav D., Pacold, Michael E., Kim, Dohoon, Birsoy, Kivanc, Chen, Walter W., Tsun, Zhi-Yang, Kalaany, Nada Y., Hsu, Peggy P., Ottina, Kathleen, Chan, Albert M., Yuan, Bingbing B., and Sabatini, David M.
- Subjects
Citric Acid Cycle ,Glutamic Acid ,Breast Neoplasms ,Biology ,medicine.disease_cause ,Gene Expression Regulation, Enzymologic ,Article ,Serine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,RNA interference ,Cell Line, Tumor ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Phosphoglycerate dehydrogenase ,Melanoma ,Phosphoglycerate Dehydrogenase ,Cell Proliferation ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Cell growth ,Cancer ,Genomics ,medicine.disease ,Molecular biology ,3. Good health ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Ketoglutaric Acids ,RNA Interference ,Carcinogenesis ,Neoplasm Transplantation - Abstract
Cancer cells adapt their metabolic processes to drive macromolecular biosynthesis for rapid cell growth and proliferation[superscript 1, 2]. RNA interference (RNAi)-based loss-of-function screening has proven powerful for the identification of new and interesting cancer targets, and recent studies have used this technology in vivo to identify novel tumour suppressor genes[superscript 3]. Here we developed a method for identifying novel cancer targets via negative-selection RNAi screening using a human breast cancer xenograft model at an orthotopic site in the mouse. Using this method, we screened a set of metabolic genes associated with aggressive breast cancer and stemness to identify those required for in vivo tumorigenesis. Among the genes identified, phosphoglycerate dehydrogenase (PHGDH) is in a genomic region of recurrent copy number gain in breast cancer and PHGDH protein levels are elevated in 70% of oestrogen receptor (ER)-negative breast cancers. PHGDH catalyses the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased serine synthesis flux. Suppression of PHGDH in cell lines with elevated PHGDH expression, but not in those without, causes a strong decrease in cell proliferation and a reduction in serine synthesis. We find that PHGDH suppression does not affect intracellular serine levels, but causes a drop in the levels of α-ketoglutarate, another output of the pathway and a tricarboxylic acid (TCA) cycle intermediate. In cells with high PHGDH expression, the serine synthesis pathway contributes approximately 50% of the total anaplerotic flux of glutamine into the TCA cycle. These results reveal that certain breast cancers are dependent upon increased serine pathway flux caused by PHGDH overexpression and demonstrate the utility of in vivo negative-selection RNAi screens for finding potential anticancer targets., Susan G. Komen Breast Cancer Foundation (Fellowship), Life Sciences Research Foundation (Fellowship), W. M. Keck Foundation, David H. Koch Cancer Research Fund, Alexander and Margaret Stewart Trust, National Institutes of Health (U.S.) (Grant CA103866)
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- 2010
29. What the web can't do
- Author
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David A. Shamma, Seth Fitzsimmonds, Ramesh Jain, Joe Gregorio, Kevin Marks, and Adam Stevens Hupp
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Web server ,Ajax ,Web development ,Web 2.0 ,business.industry ,Computer science ,Dynamic web page ,computer.software_genre ,JavaScript ,Web API ,World Wide Web ,Web page ,Web design ,Web application ,Web service ,business ,computer ,computer.programming_language - Abstract
This panel discusses how polling in the HTTPd protocol affects how we are building the next generation of the web and its applications. As other technologies (HTML, Javascript, etc.) move forward, we ask should the web's protocol also evolve or is it sufficient for the web to continue through just GET and POST?
- Published
- 2010
30. Abstract LB-129: Evidence from expression profiling, proteomics, metabolomics and FDG-PET of an estrogen-dependent metabolic switch in tuberin-null cells
- Author
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Yang Sun, Erik Zhang, Mi-Ae Park, Edward M. Driggers, Kevin Marks, Simon T. Dillon, Victor H. Gerbaudo, Chenggang Li, Towia A. Libermann, Manoj Bhasin, Jane J. Yu, Elizabeth P. Henske, Shuyan Wang, and Tasha Morrison
- Subjects
Cancer Research ,medicine.drug_class ,Cell ,Lipid metabolism ,mTORC1 ,Biology ,PKM2 ,Molecular biology ,Gene expression profiling ,medicine.anatomical_structure ,Isocitrate dehydrogenase ,Oncology ,Estrogen ,medicine ,Null cell - Abstract
Lymphangioleiomyomatosis (LAM) is a female predominant lung disease characterized by widely-distributed nodules of ‘LAM’ cells and progressive cyst formation that leads to respiratory failure. LAM cells typically have mutation or inactivation of TSC2, leading to mTORC1 activation. We previously demonstrated that estrogen promotes the survival of tuberin-deficient ELT3 cells both in vitro and in vivo, and that estrogen treatment of mice bearing ELT3 cells xenograft tumors promotes lung metastasis. This estrogen-induced cell survival and metastasis was inhibited in vivo by the MEK inhibitor CI-1040. To elucidate pro-survival events mediated by estrogen in tuberin-null cells, we compared Tsc2-null ELT3 cell xenograft tumors from estrogen or placebo-treated mice using expression profiling and proteomic analysis . Expression profiling of ELT3 cell xenograft tumors revealed that estrogen upregulates the expression of genes in lipid and amino acid metabolism pathways. Among these genes, the estrogen-induced expression of amino adipatetransferase (AADAT), which is involved in lysine degradation, has been confirmed by immunoblotting of tumor lysates. Using iTRAQ proteomics from ELT3 xenograft tumors, we identified 40 proteins that are significantly regulated by estrogen, including proteins involved in carbohydrate metabolism (creatine kinase), amino acid degradation (aspartate aminotransferase) and lipid metabolism (isocitrate dehydrogenase). Metabolic profiling by LC/MS/MS of TSC2-null angiomyolipoma-derived cells from a LAM patient (621-101 cells) showed a temporal effect of rapamycin (10 nM) on the accumulation of pentose phosphate pathway intermediates and glycolytic metabolites. Cellular amino acid levels were reduced after rapamycin treatment. Consistent with a metabolic switch occurring in LAM, we found, using IHC staining, that the tumor-associated PKM2 is abundantly expressed in ELT3 cell xenograft tumors, lung metastatic lesions from estrogen-treated mice bearing ELT3 cell xenograft tumors, and in human LAM cell nodules. Finally, using FDG-PET, we found that xenograft ELT3 cell tumors in estrogen-treated mice exhibited higher levels of uptake compared with placebo-treated mice. In conclusion, gene expression profiling indicated that estrogen enhances the expression of genes which products regulate glucose and amino acid metabolism. Proteomic analysis showed estrogen-regulated candidates involved in glycolysis, amino acid, and lipid metabolisms. Metabolomic screening revealed that cells lacking tuberin have a metabolic response to rapamycin treatment. FDG-PET imaging showed enhanced uptake in estrogen-treated xenograft tumors. Collectively, these data indicate that cellular metabolic alterations may contribute to the pathogenesis of LAM. Targeting metabolic regulators might have therapeutic benefit for LAM. Citation Format: Yang Sun, Chenggang Li, Kevin Marks, Erik Zhang, Tasha Morrison, Mi-Ae Park, Shuyan Wang, Simon Dillon, Manoj Bhasin, Towia Libermann, Edward Driggers, Victor Gerbaudo, Elizabeth Petri Henske, Jane Yu. Evidence from expression profiling, proteomics, metabolomics and FDG-PET of an estrogen-dependent metabolic switch in tuberin-null cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-129. doi:10.1158/1538-7445.AM2013-LB-129
- Published
- 2013
31. Abstract 1002: Induced dependency on amino acid metabolism in proliferating cancer cells upon PKM2 activation
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Jeff Hixon, Shaohui Wang, Hin Koon Woo, Charles Kung, Francesco G. Salituro, Stefan Gross, Ed Driggers, Stuart Murray, Yi Gao, Hua Yang, Shengfang Jin, Fang Cheng, Katherine Yen, Jeffrey O. Saunders, Xiling Wang, Sung Choe, Michael Su, Lenny Dang, and Kevin Marks
- Subjects
Serine ,Cancer Research ,Metabolic pathway ,Oncology ,Biochemistry ,Cell growth ,Anaerobic glycolysis ,Cancer cell ,Glycolysis ,Biology ,PKM2 ,Pyruvate kinase ,Cell biology - Abstract
It is well recognized that proliferating tumor cells invariably utilize aerobic glycolysis to support their high metabolic demands. Recent studies have further elucidated the paradoxical observation that this increase in glycolysis in proliferating tumor cells is often coupled with a molecular switch from the constitutively high activity PKM1 isoform to the modulated lower activity PKM2 isoform1,2, effectively constraining lower glycolysis at the last pyruvate kinase step. Here, we report an unanticipated link between glucose metabolism and amino-acid metabolic pathways in cancer cells. We characterized the biochemical and cellular effects of a small-molecule allosteric activator of the M2 isoform of pyruvate kinase (AGX-257) in various cancer cell types. We demonstrate that activation of PKM2 results in a metabolic rewiring of specific cancer cells that results in a profound dependency on the presence of the normally non-essential amino acid serine for continued cell proliferation. The induced serine auxotrophy by PKM2 activation is concomitant with reduced flux through the endogenous serine biosynthetic pathway and increased levels of high affinity serine transporters. PKM2 activators, possibly in combination with agents that modulate the cellular and extracellular serine pools, could form the basis for a new approach toward developing therapy for treating cancer. References: 1 Christofk, H. R. et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230-233 (2008). 2 Clower, C. V. et al. The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. Proc Natl Acad Sci U S A 107, 1894-1899 (2010). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1002. doi:1538-7445.AM2012-1002
- Published
- 2012
32. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
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Bryson D. Bennett, Lewis C. Cantley, Robert M. Prins, Lenny Dang, Kevin Marks, Valeria Fantin, Joshua D. Rabinowitz, Marie C. Keenan, Shinsan M. Su, Patrick S. Ward, David W. White, Linda M. Liau, Mark A. Bittinger, Shengfang Jin, Katharine E. Yen, Craig B. Thompson, Edward M. Driggers, Stefan Gross, Matthew G. Vander Heiden, and Hyun Gyung Jang
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Models, Molecular ,IDH1 ,Protein Conformation ,Enasidenib ,medicine.disease_cause ,Arginine ,Crystallography, X-Ray ,IDH2 ,Article ,Cell Line ,Glutarates ,Catalytic Domain ,Neoplasms ,medicine ,Humans ,Histidine ,Oxidative decarboxylation ,Enzyme Assays ,Mutation ,Multidisciplinary ,biology ,Chemistry ,Brain Neoplasms ,Age Factors ,Active site ,Glioma ,Isocitrate Dehydrogenase ,Isocitrate dehydrogenase ,Biochemistry ,biology.protein ,Disease Progression ,Ketoglutaric Acids ,Mutant Proteins ,Carcinogenesis - Abstract
Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme's ability to catalyse conversion of isocitrate to alpha-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.
- Published
- 2010
33. The medical illustrator and educational technology
- Author
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Kevin Marks
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Rational system ,Multimedia ,Audiovisual Aids ,Education, Medical ,business.industry ,Educational technology ,General Medicine ,Graphic design ,computer.software_genre ,Term (time) ,England ,Medical Illustration ,Medicine ,business ,computer - Abstract
This paper discusses the definition and application of educational technology, how its development from a concept to a rational system in everyday use has affected the medical illustrator and what type of relationship educational technology and the medical illustrator will enjoy in the future.(The term ‘medical illustrator’ is used here to mean people working in medical art and graphic design. However, the views put forward have implications for all who come under the broader generic use of the term ‘medical illustrator’.)
- Published
- 1981
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