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2. Assigning functionality to cysteines by base editing of cancer dependency genes

Author

Li, Haoxin, Ma, Tiantai, Remsberg, Jarrett R, Won, Sang Joon, DeMeester, Kristen E, Njomen, Evert, Ogasawara, Daisuke, Zhao, Kevin T, Huang, Tony P, Lu, Bingwen, Simon, Gabriel M, Melillo, Bruno, Schreiber, Stuart L, Lykke-Andersen, Jens, Liu, David R, and Cravatt, Benjamin F

Subjects
Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Biological Sciences, Genetics, Biotechnology, Cancer, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Humans, Cysteine, Proteomics, Gene Editing, Proteome, Neoplasms, Nuclear Proteins, Medicinal and Biomolecular Chemistry, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medicinal and biomolecular chemistry
Abstract

Covalent chemistry represents an attractive strategy for expanding the ligandability of the proteome, and chemical proteomics has revealed numerous electrophile-reactive cysteines on diverse human proteins. Determining which of these covalent binding events affect protein function, however, remains challenging. Here we describe a base-editing strategy to infer the functionality of cysteines by quantifying the impact of their missense mutation on cancer cell proliferation. The resulting atlas, which covers more than 13,800 cysteines on more than 1,750 cancer dependency proteins, confirms the essentiality of cysteines targeted by covalent drugs and, when integrated with chemical proteomic data, identifies essential, ligandable cysteines in more than 160 cancer dependency proteins. We further show that a stereoselective and site-specific ligand targeting an essential cysteine in TOE1 inhibits the nuclease activity of this protein through an apparent allosteric mechanism. Our findings thus describe a versatile method and valuable resource to prioritize the pursuit of small-molecule probes with high function-perturbing potential.

Published
2023

5. Author Correction: Diversity-oriented synthesis encoded by deoxyoligonucleotides

Author

Hudson, Liam, Mason, Jeremy W., Westphal, Matthias V., Richter, Matthieu J. R., Thielman, Jonathan R., Hua, Bruce K., Gerry, Christopher J., Xia, Guoqin, Osswald, Heather L., Knapp, John M., Tan, Zher Yin, Kokkonda, Praveen, Tresco, Ben I. C., Liu, Shuang, Reidenbach, Andrew G., Lim, Katherine S., Poirier, Jennifer, Capece, John, Bonazzi, Simone, Gampe, Christian M., Smith, Nichola J., Bradner, James E., Coley, Connor W., Clemons, Paul A., Melillo, Bruno, Hon, C. Suk-Yee, Ottl, Johannes, Dumelin, Christoph E., Schaefer, Jonas V., Faust, Ann Marie E., Berst, Frédéric, Schreiber, Stuart L., Zécri, Frédéric J., and Briner, Karin

Published
2023
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6. Diversity-oriented synthesis encoded by deoxyoligonucleotides

Author

Hudson, Liam, Mason, Jeremy W., Westphal, Matthias V., Richter, Matthieu J. R., Thielman, Jonathan R., Hua, Bruce K., Gerry, Christopher J., Xia, Guoqin, Osswald, Heather L., Knapp, John M., Tan, Zher Yin, Kokkonda, Praveen, Tresco, Ben I. C., Liu, Shuang, Reidenbach, Andrew G., Lim, Katherine S., Poirier, Jennifer, Capece, John, Bonazzi, Simone, Gampe, Christian M., Smith, Nichola J., Bradner, James E., Coley, Connor W., Clemons, Paul A., Melillo, Bruno, Hon, C. Suk-Yee, Ottl, Johannes, Dumelin, Christoph E., Schaefer, Jonas V., Faust, Ann Marie E., Berst, Frédéric, Schreiber, Stuart L., Zécri, Frédéric J., and Briner, Karin

Published
2023
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7. Reference compounds for characterizing cellular injury in high-content cellular morphology assays

Author

Dahlin, Jayme L., Hua, Bruce K., Zucconi, Beth E., Nelson, Jr, Shawn D., Singh, Shantanu, Carpenter, Anne E., Shrimp, Jonathan H., Lima-Fernandes, Evelyne, Wawer, Mathias J., Chung, Lawrence P. W., Agrawal, Ayushi, O’Reilly, Mary, Barsyte-Lovejoy, Dalia, Szewczyk, Magdalena, Li, Fengling, Lak, Parnian, Cuellar, Matthew, Cole, Philip A., Meier, Jordan L., Thomas, Tim, Baell, Jonathan B., Brown, Peter J., Walters, Michael A., Clemons, Paul A., Schreiber, Stuart L., and Wagner, Bridget K.

Published
2023
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8. Mapping the landscape of genetic dependencies in chordoma

Author

Sharifnia, Tanaz, Wawer, Mathias J., Goodale, Amy, Lee, Yenarae, Kazachkova, Mariya, Dempster, Joshua M., Muller, Sandrine, Levy, Joan, Freed, Daniel M., Sommer, Josh, Kalfon, Jérémie, Vazquez, Francisca, Hahn, William C., Root, David E., Clemons, Paul A., and Schreiber, Stuart L.

Published
2023
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9. An expanded universe of cancer targets.

Author

Hahn, William C, Bader, Joel S, Braun, Theodore P, Califano, Andrea, Clemons, Paul A, Druker, Brian J, Ewald, Andrew J, Fu, Haian, Jagu, Subhashini, Kemp, Christopher J, Kim, William, Kuo, Calvin J, McManus, Michael, B Mills, Gordon, Mo, Xiulei, Sahni, Nidhi, Schreiber, Stuart L, Talamas, Jessica A, Tamayo, Pablo, Tyner, Jeffrey W, Wagner, Bridget K, Weiss, William A, Gerhard, Daniela S, and Cancer Target Discovery and Development Network

Subjects
Cancer Target Discovery and Development Network, Animals, Humans, Neoplasms, Disease Models, Animal, Drug Delivery Systems, Genomics, Tumor Escape, Clinical Trials as Topic, Tumor Microenvironment, Biotechnology, Rare Diseases, Cancer, Orphan Drug, Genetics, 2.1 Biological and endogenous factors, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

The characterization of cancer genomes has provided insight into somatically altered genes across tumors, transformed our understanding of cancer biology, and enabled tailoring of therapeutic strategies. However, the function of most cancer alleles remains mysterious, and many cancer features transcend their genomes. Consequently, tumor genomic characterization does not influence therapy for most patients. Approaches to understand the function and circuitry of cancer genes provide complementary approaches to elucidate both oncogene and non-oncogene dependencies. Emerging work indicates that the diversity of therapeutic targets engendered by non-oncogene dependencies is much larger than the list of recurrently mutated genes. Here we describe a framework for this expanded list of cancer targets, providing novel opportunities for clinical translation.

Published
2021

10. Beth Levine in memoriam

Author

An, Zhenyi, Ballabio, Andrea, Bennett, Lynda, Boya, Patricia, Cecconi, Francesco, Chiang, Wei-Chung, Codogno, Patrice, Colombo, Maria Isabel, Cuervo, Ana Maria, Debnath, Jayanta, Deretic, Vojo, Dikic, Ivan, Dionne, Keith, Dong, Xiaonan, Elazar, Zvulun, Galluzzi, Lorenzo, Gentile, Frank, Griffin, Diane E, Hansen, Malene, Hardwick, J Marie, He, Congcong, Huang, Shu-Yi, Hurley, James, Jackson, William T, Jozefiak, Cindy, Kitsis, Richard N, Klionsky, Daniel J, Kroemer, Guido, Meijer, Alfred J, Melendez, Alicia, Melino, Gerry, Mizushima, Noboru, Murphy, Leon O, Nixon, Ralph, Orvedahl, Anthony, Pattingre, Sophie, Piacentini, Mauro, Reggiori, Fulvio, Ross, Theodora, Rubinsztein, David C, Ryan, Kevin, Sadoshima, Junichi, Schreiber, Stuart L, Scott, Frederick, Sebti, Salwa, Shiloh, Michael, Shoji, Sanae, Simonsen, Anne, Smith, Haley, Sumpter, Kathryn M, Thompson, Craig B, Thorburn, Andrew, Thumm, Michael, Tooze, Sharon, Vaccaro, Maria I, Virgin, Herbert W, Wang, Fei, White, Eileen, Xavier, Ramnik J, Yoshimori, Tamotsu, Yuan, Junying, Yue, Zhenyu, and Zhong, Qing

Subjects
Biochemistry and Cell Biology, Biological Sciences, Biochemistry & Molecular Biology, Biochemistry and cell biology
Published
2020

13. Bicyclic Pyrrolidine Inhibitors of Toxoplasma gondii Phenylalanine t-RNA Synthetase with Antiparasitic Potency In Vitro and Brain Exposure

Author

Ence, Chloe C., primary, Uddin, Taher, additional, Borrel, Julien, additional, Mittal, Payal, additional, Xie, Han, additional, Zoller, Jochen, additional, Sharma, Amit, additional, Comer, Eamon, additional, Schreiber, Stuart L., additional, Melillo, Bruno, additional, Sibley, L. David, additional, and Chatterjee, Arnab K., additional

Published
2024
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15. A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles

Author

Subramanian, Aravind, Narayan, Rajiv, Corsello, Steven M, Peck, David D, Natoli, Ted E, Lu, Xiaodong, Gould, Joshua, Davis, John F, Tubelli, Andrew A, Asiedu, Jacob K, Lahr, David L, Hirschman, Jodi E, Liu, Zihan, Donahue, Melanie, Julian, Bina, Khan, Mariya, Wadden, David, Smith, Ian C, Lam, Daniel, Liberzon, Arthur, Toder, Courtney, Bagul, Mukta, Orzechowski, Marek, Enache, Oana M, Piccioni, Federica, Johnson, Sarah A, Lyons, Nicholas J, Berger, Alice H, Shamji, Alykhan F, Brooks, Angela N, Vrcic, Anita, Flynn, Corey, Rosains, Jacqueline, Takeda, David Y, Hu, Roger, Davison, Desiree, Lamb, Justin, Ardlie, Kristin, Hogstrom, Larson, Greenside, Peyton, Gray, Nathanael S, Clemons, Paul A, Silver, Serena, Wu, Xiaoyun, Zhao, Wen-Ning, Read-Button, Willis, Wu, Xiaohua, Haggarty, Stephen J, Ronco, Lucienne V, Boehm, Jesse S, Schreiber, Stuart L, Doench, John G, Bittker, Joshua A, Root, David E, Wong, Bang, and Golub, Todd R

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Aetiology, 2.1 Biological and endogenous factors, Cell Line, Tumor, Drug Resistance, Neoplasm, Gene Expression Profiling, Humans, Neoplasms, Organ Specificity, Pharmaceutical Preparations, Sequence Analysis, RNA, Small Molecule Libraries, Functional genomics, chemical biology, gene expression profiling, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

We previously piloted the concept of a Connectivity Map (CMap), whereby genes, drugs, and disease states are connected by virtue of common gene-expression signatures. Here, we report more than a 1,000-fold scale-up of the CMap as part of the NIH LINCS Consortium, made possible by a new, low-cost, high-throughput reduced representation expression profiling method that we term L1000. We show that L1000 is highly reproducible, comparable to RNA sequencing, and suitable for computational inference of the expression levels of 81% of non-measured transcripts. We further show that the expanded CMap can be used to discover mechanism of action of small molecules, functionally annotate genetic variants of disease genes, and inform clinical trials. The 1.3 million L1000 profiles described here, as well as tools for their analysis, are available at https://clue.io.

Published
2017

16. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition

Author

Hangauer, Matthew J, Viswanathan, Vasanthi S, Ryan, Matthew J, Bole, Dhruv, Eaton, John K, Matov, Alexandre, Galeas, Jacqueline, Dhruv, Harshil D, Berens, Michael E, Schreiber, Stuart L, McCormick, Frank, and McManus, Michael T

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Animals, Antioxidants, Apoptosis, Drug Evaluation, Preclinical, Drug Resistance, Neoplasm, Female, Glutathione Peroxidase, Humans, Iron, Male, Mesoderm, Mice, Molecular Targeted Therapy, Neoplasms, Phospholipid Hydroperoxide Glutathione Peroxidase, Recurrence, Xenograft Model Antitumor Assays, General Science & Technology
Abstract

Acquired drug resistance prevents cancer therapies from achieving stable and complete responses. Emerging evidence implicates a key role for non-mutational drug resistance mechanisms underlying the survival of residual cancer 'persister' cells. The persister cell pool constitutes a reservoir from which drug-resistant tumours may emerge. Targeting persister cells therefore presents a therapeutic opportunity to impede tumour relapse. We previously found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival. Here we show that a similar therapy-resistant cell state underlies the behaviour of persister cells derived from a wide range of cancers and drug treatments. Consequently, we demonstrate that persister cells acquire a dependency on GPX4. Loss of GPX4 function results in selective persister cell ferroptotic death in vitro and prevents tumour relapse in mice. These findings suggest that targeting of GPX4 may represent a therapeutic strategy to prevent acquired drug resistance.

Published
2017

17. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway

Author

Viswanathan, Vasanthi S, Ryan, Matthew J, Dhruv, Harshil D, Gill, Shubhroz, Eichhoff, Ossia M, Seashore-Ludlow, Brinton, Kaffenberger, Samuel D, Eaton, John K, Shimada, Kenichi, Aguirre, Andrew J, Viswanathan, Srinivas R, Chattopadhyay, Shrikanta, Tamayo, Pablo, Yang, Wan Seok, Rees, Matthew G, Chen, Sixun, Boskovic, Zarko V, Javaid, Sarah, Huang, Cherrie, Wu, Xiaoyun, Tseng, Yuen-Yi, Roider, Elisabeth M, Gao, Dong, Cleary, James M, Wolpin, Brian M, Mesirov, Jill P, Haber, Daniel A, Engelman, Jeffrey A, Boehm, Jesse S, Kotz, Joanne D, Hon, Cindy S, Chen, Yu, Hahn, William C, Levesque, Mitchell P, Doench, John G, Berens, Michael E, Shamji, Alykhan F, Clemons, Paul A, Stockwell, Brent R, and Schreiber, Stuart L

Subjects
Cancer, Cadherins, Cell Death, Cell Line, Tumor, Cell Lineage, Cell Transdifferentiation, Drug Resistance, Neoplasm, Epithelial-Mesenchymal Transition, Glutathione Peroxidase, Humans, Iron, Lipid Peroxidation, Lipid Peroxides, Male, Melanoma, Mesoderm, Neoplasms, Phospholipid Hydroperoxide Glutathione Peroxidase, Prostatic Neoplasms, Proteomics, Proto-Oncogene Proteins B-raf, Reproducibility of Results, Zinc Finger E-box-Binding Homeobox 1, General Science & Technology
Abstract

Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial-mesenchymal transition in epithelial-derived carcinomas, TGFβ-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.

Published
2017

18. Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity

Author

Sheppard, Hadley E., Dall’Agnese, Alessandra, Park, Woojun D., Shamim, M. Hamza, Dubrulle, Julien, Johnson, Hannah L., Stossi, Fabio, Cogswell, Patricia, Sommer, Josh, Levy, Joan, Sharifnia, Tanaz, Wawer, Mathias J., Nabet, Behnam, Gray, Nathanael S., Clemons, Paul A., Schreiber, Stuart L., Workman, Paul, Young, Richard A., and Lin, Charles Y.

Published
2021
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22. Chemical tools to expand the ligandable proteome: diversity-oriented synthesis-based photoreactive stereoprobes

Author

Ogasawara, Daisuke, primary, Konrad, David B., additional, Tan, Zher Yin, additional, Carey, Kimberly L., additional, Luo, Jessica, additional, Won, Sang Joon, additional, Li, Haoxin, additional, Carter, Trever, additional, DeMeester, Kristen E., additional, Njomen, Evert, additional, Schreiber, Stuart L., additional, Xavier, Ramnik J., additional, Melillo, Bruno, additional, and Cravatt, Benjamin F., additional

Published
2024
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23. Bicyclic pyrrolidine inhibitors ofToxoplasma gondiiphenylalanine t-RNA synthetase with antiparasitic potencyin vitroand brain exposure

Author

Ence, Chloe C., primary, Uddin, Taher, additional, Borrel, Julien, additional, Mittal, Payal, additional, Xie, Han, additional, Zoller, Jochen, additional, Sharma, Amit, additional, Comer, Eamon, additional, Schreiber, Stuart L., additional, Melillo, Bruno, additional, Sibley, L. David, additional, and Chatterjee, Arnab K., additional

Published
2024
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24. High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines

Author

Yu, Channing, Mannan, Aristotle M, Yvone, Griselda Metta, Ross, Kenneth N, Zhang, Yan-Ling, Marton, Melissa A, Taylor, Bradley R, Crenshaw, Andrew, Gould, Joshua Z, Tamayo, Pablo, Weir, Barbara A, Tsherniak, Aviad, Wong, Bang, Garraway, Levi A, Shamji, Alykhan F, Palmer, Michelle A, Foley, Michael A, Winckler, Wendy, Schreiber, Stuart L, Kung, Andrew L, and Golub, Todd R

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Animals, Cell Line, Tumor, DNA Barcoding, Taxonomic, Drug Resistance, Neoplasm, Genotyping Techniques, High-Throughput Nucleotide Sequencing, Humans, Mice, Neoplasms
Abstract

Hundreds of genetically characterized cell lines are available for the discovery of genotype-specific cancer vulnerabilities. However, screening large numbers of compounds against large numbers of cell lines is currently impractical, and such experiments are often difficult to control. Here we report a method called PRISM that allows pooled screening of mixtures of cancer cell lines by labeling each cell line with 24-nucleotide barcodes. PRISM revealed the expected patterns of cell killing seen in conventional (unpooled) assays. In a screen of 102 cell lines across 8,400 compounds, PRISM led to the identification of BRD-7880 as a potent and highly specific inhibitor of aurora kinases B and C. Cell line pools also efficiently formed tumors as xenografts, and PRISM recapitulated the expected pattern of erlotinib sensitivity in vivo.

Published
2016

25. High-Throughput Assay and Discovery of Small Molecules that Interrupt Malaria Transmission

Author

Plouffe, David M, Wree, Melanie, Du, Alan Y, Meister, Stephan, Li, Fengwu, Patra, Kailash, Lubar, Aristea, Okitsu, Shinji L, Flannery, Erika L, Kato, Nobutaka, Tanaseichuk, Olga, Comer, Eamon, Zhou, Bin, Kuhen, Kelli, Zhou, Yingyao, Leroy, Didier, Schreiber, Stuart L, Scherer, Christina A, Vinetz, Joseph, and Winzeler, Elizabeth A

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Malaria, Vector-Borne Diseases, Infectious Diseases, HIV/AIDS, Rare Diseases, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Infection, Good Health and Well Being, Antimalarials, Drug Evaluation, Preclinical, High-Throughput Screening Assays, Humans, Plasmodium falciparum, Plasmodium, chemotherapy, gametocytes, malaria, transmission, Microbiology, Immunology, Biochemistry and cell biology, Medical microbiology
Abstract

Preventing transmission is an important element of malaria control. However, most of the current available methods to assay for malaria transmission blocking are relatively low throughput and cannot be applied to large chemical libraries. We have developed a high-throughput and cost-effective assay, the Saponin-lysis Sexual Stage Assay (SaLSSA), for identifying small molecules with transmission-blocking capacity. SaLSSA analysis of 13,983 unique compounds uncovered that >90% of well-characterized antimalarials, including endoperoxides and 4-aminoquinolines, as well as compounds active against asexual blood stages, lost most of their killing activity when parasites developed into metabolically quiescent stage V gametocytes. On the other hand, we identified compounds with consistent low nanomolar transmission-blocking activity, some of which showed cross-reactivity against asexual blood and liver stages. The data clearly emphasize substantial physiological differences between sexual and asexual parasites and provide a tool and starting points for the discovery and development of transmission-blocking drugs.

Published
2016

26. Modular, stereocontrolled C β –H/C α –C activation of alkyl carboxylic acids

Author

Shang, Ming, Feu, Karla S., Vantourout, Julien C., Barton, Lisa M., Osswald, Heather L., Kato, Nobutaka, Gagaring, Kerstin, McNamara, Case W., Chen, Gang, Hu, Liang, Ni, Shengyang, Fernández-Canelas, Paula, Chen, Miao, Merchant, Rohan R., Qin, Tian, Schreiber, Stuart L., Melillo, Bruno, Yu, Jin-Quan, and Baran, Phil S.

Published
2019

29. Plasticity of ether lipids promotes ferroptosis susceptibility and evasion

Author

Zou, Yilong, Henry, Whitney S., Ricq, Emily L., Graham, Emily T., Phadnis, Vaishnavi V., Maretich, Pema, Paradkar, Sateja, Boehnke, Natalie, Deik, Amy A., Reinhardt, Ferenc, Eaton, John K., Ferguson, Bryan, Wang, Wenyu, Fairman, Joshua, Keys, Heather R., Dančík, Vlado, Clish, Clary B., Clemons, Paul A., Hammond, Paula T., Boyer, Laurie A., Weinberg, Robert A., and Schreiber, Stuart L.

Published
2020
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30. Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles

Author

Eaton, John K., Furst, Laura, Ruberto, Richard A., Moosmayer, Dieter, Hilpmann, André, Ryan, Matthew J., Zimmermann, Katja, Cai, Luke L., Niehues, Michael, Badock, Volker, Kramm, Anneke, Chen, Sixun, Hillig, Roman C., Clemons, Paul A., Gradl, Stefan, Montagnon, Claire, Lazarski, Kiel E., Christian, Sven, Bajrami, Besnik, Neuhaus, Roland, Eheim, Ashley L., Viswanathan, Vasanthi S., and Schreiber, Stuart L.

Published
2020
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32. The promise and peril of chemical probes

Author

Arrowsmith, Cheryl H, Audia, James E, Austin, Christopher, Baell, Jonathan, Bennett, Jonathan, Blagg, Julian, Bountra, Chas, Brennan, Paul E, Brown, Peter J, Bunnage, Mark E, Buser-Doepner, Carolyn, Campbell, Robert M, Carter, Adrian J, Cohen, Philip, Copeland, Robert A, Cravatt, Ben, Dahlin, Jayme L, Dhanak, Dashyant, Edwards, Aled M, Frederiksen, Mathias, Frye, Stephen V, Gray, Nathanael, Grimshaw, Charles E, Hepworth, David, Howe, Trevor, Huber, Kilian VM, Jin, Jian, Knapp, Stefan, Kotz, Joanne D, Kruger, Ryan G, Lowe, Derek, Mader, Mary M, Marsden, Brian, Mueller-Fahrnow, Anke, Müller, Susanne, O'Hagan, Ronan C, Overington, John P, Owen, Dafydd R, Rosenberg, Saul H, Ross, Ruth, Roth, Bryan, Schapira, Matthieu, Schreiber, Stuart L, Shoichet, Brian, Sundström, Michael, Superti-Furga, Giulio, Taunton, Jack, Toledo-Sherman, Leticia, Walpole, Chris, Walters, Michael A, Willson, Timothy M, Workman, Paul, Young, Robert N, and Zuercher, William J

Subjects
Generic health relevance, Biomedical Research, Humans, Information Dissemination, Intellectual Property, Internet, Molecular Probes, Molecular Weight, Sensitivity and Specificity, Small Molecule Libraries, Medicinal and Biomolecular Chemistry, Biochemistry and Cell Biology, Biochemistry & Molecular Biology
Abstract

Chemical probes are powerful reagents with increasing impacts on biomedical research. However, probes of poor quality or that are used incorrectly generate misleading results. To help address these shortcomings, we will create a community-driven wiki resource to improve quality and convey current best practice.

Published
2015

33. Linking Tumor Mutations to Drug Responses via a Quantitative Chemical–Genetic Interaction Map

Author

Martins, Maria M, Zhou, Alicia Y, Corella, Alexandra, Horiuchi, Dai, Yau, Christina, Rakhshandehroo, Taha, Gordan, John D, Levin, Rebecca S, Johnson, Jeff, Jascur, John, Shales, Mike, Sorrentino, Antonio, Cheah, Jaime, Clemons, Paul A, Shamji, Alykhan F, Schreiber, Stuart L, Krogan, Nevan J, Shokat, Kevan M, McCormick, Frank, Goga, Andrei, and Bandyopadhyay, Sourav

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Cancer, Health Disparities, Human Genome, Women's Health, Cancer Genomics, Biotechnology, Precision Medicine, Breast Cancer, Aetiology, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Generic health relevance, Good Health and Well Being, Animals, Breast Neoplasms, Cell Line, Tumor, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Female, Genomics, High-Throughput Screening Assays, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Mutation, Random Allocation, Signal Transduction, Xenograft Model Antitumor Assays, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

UnlabelledThere is an urgent need in oncology to link molecular aberrations in tumors with therapeutics that can be administered in a personalized fashion. One approach identifies synthetic-lethal genetic interactions or dependencies that cancer cells acquire in the presence of specific mutations. Using engineered isogenic cells, we generated a systematic and quantitative chemical-genetic interaction map that charts the influence of 51 aberrant cancer genes on 90 drug responses. The dataset strongly predicts drug responses found in cancer cell line collections, indicating that isogenic cells can model complex cellular contexts. Applying this dataset to triple-negative breast cancer, we report clinically actionable interactions with the MYC oncogene, including resistance to AKT-PI3K pathway inhibitors and an unexpected sensitivity to dasatinib through LYN inhibition in a synthetic lethal manner, providing new drug and biomarker pairs for clinical investigation. This scalable approach enables the prediction of drug responses from patient data and can accelerate the development of new genotype-directed therapies.SignificanceDetermining how the plethora of genomic abnormalities that exist within a given tumor cell affects drug responses remains a major challenge in oncology. Here, we develop a new mapping approach to connect cancer genotypes to drug responses using engineered isogenic cell lines and demonstrate how the resulting dataset can guide clinical interrogation.

Published
2015

36. Chemical Proteomic Discovery of Isotype‐Selective Covalent Inhibitors of the RNA Methyltransferase NSUN2

Author

Tao, Yongfeng, primary, Felber, Jan G., additional, Zou, Zhongyu, additional, Njomen, Evert, additional, Remsberg, Jarrett R., additional, Ogasawara, Daisuke, additional, Ye, Chang, additional, Melillo, Bruno, additional, Schreiber, Stuart L., additional, He, Chuan, additional, Remillard, David, additional, and Cravatt, Benjamin F., additional

Published
2023
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37. Rational Screening for Cooperativity in Small-Molecule Inducers of Protein–Protein Associations

Author

Liu, Shuang, primary, Tong, Bingqi, additional, Mason, Jeremy W., additional, Ostrem, Jonathan M., additional, Tutter, Antonin, additional, Hua, Bruce K., additional, Tang, Sunny A., additional, Bonazzi, Simone, additional, Briner, Karin, additional, Berst, Frédéric, additional, Zécri, Frédéric J., additional, and Schreiber, Stuart L., additional

Published
2023
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38. The landscape of cancer cell line metabolism

Author

Li, Haoxin, Ning, Shaoyang, Ghandi, Mahmoud, Kryukov, Gregory V., Gopal, Shuba, Deik, Amy, Souza, Amanda, Pierce, Kerry, Keskula, Paula, Hernandez, Desiree, Ann, Julie, Shkoza, Dojna, Apfel, Verena, Zou, Yilong, Vazquez, Francisca, Barretina, Jordi, Pagliarini, Raymond A., Galli, Giorgio G., Root, David E., Hahn, William C., Tsherniak, Aviad, Giannakis, Marios, Schreiber, Stuart L., Clish, Clary B., Garraway, Levi A., and Sellers, William R.

Published
2019
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39. Small-molecule targeting of brachyury transcription factor addiction in chordoma

Author

Sharifnia, Tanaz, Wawer, Mathias J., Chen, Ting, Huang, Qing-Yuan, Weir, Barbara A., Sizemore, Ann, Lawlor, Matthew A., Goodale, Amy, Cowley, Glenn S., Vazquez, Francisca, Ott, Christopher J., Francis, Joshua M., Sassi, Slim, Cogswell, Patricia, Sheppard, Hadley E., Zhang, Tinghu, Gray, Nathanael S., Clarke, Paul A., Blagg, Julian, Workman, Paul, Sommer, Josh, Hornicek, Francis, Root, David E., Hahn, William C., Bradner, James E., Wong, Kwok K., Clemons, Paul A., Lin, Charles Y., Kotz, Joanne D., and Schreiber, Stuart L.

Published
2019
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47. Using expression and genotype to predict drug response in yeast.

Author

Ruderfer, Douglas M, Roberts, David C, Schreiber, Stuart L, Perlstein, Ethan O, and Kruglyak, Leonid

Subjects
RNA, Messenger, Genetic Markers, Reproducibility of Results, Drug Evaluation, Preclinical, Gene Expression Profiling, Computational Biology, Genomics, Gene Expression Regulation, Fungal, Genotype, Chemistry, Pharmaceutical, Algorithms, Genetic Linkage, Chemistry, Pharmaceutical, Drug Evaluation, Preclinical, Gene Expression Regulation, Fungal, RNA, Messenger, General Science & Technology
Abstract

Personalized, or genomic, medicine entails tailoring pharmacological therapies according to individual genetic variation at genomic loci encoding proteins in drug-response pathways. It has been previously shown that steady-state mRNA expression can be used to predict the drug response (i.e., sensitivity or resistance) of non-genotyped mammalian cancer cell lines to chemotherapeutic agents. In a real-world setting, clinicians would have access to both steady-state expression levels of patient tissue(s) and a patient's genotypic profile, and yet the predictive power of transcripts versus markers is not well understood. We have previously shown that a collection of genotyped and expression-profiled yeast strains can provide a model for personalized medicine. Here we compare the predictive power of 6,229 steady-state mRNA transcript levels and 2,894 genotyped markers using a pattern recognition algorithm. We were able to predict with over 70% accuracy the drug sensitivity of 104 individual genotyped yeast strains derived from a cross between a laboratory strain and a wild isolate. We observe that, independently of drug mechanism of action, both transcripts and markers can accurately predict drug response. Marker-based prediction is usually more accurate than transcript-based prediction, likely reflecting the genetic determination of gene expression in this cross.

Published
2009

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