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40 results on '"Pantel, Sasha"'

1. Resistance to Epigenetic-Targeted Therapy Engenders Tumor Cell Vulnerabilities Associated with Enhancer Remodeling

Author

Iniguez, Amanda Balboni, Alexe, Gabriela, Wang, Emily Jue, Roti, Giovanni, Patel, Sarvagna, Chen, Liying, Kitara, Samuel, Conway, Amy, Robichaud, Amanda L, Stolte, Björn, Bandopadhayay, Pratiti, Goodale, Amy, Pantel, Sasha, Lee, Yenarae, Cheff, Dorian M, Hall, Matthew D, Guha, Rajarshi, Davis, Mindy I, Menard, Marie, Nasholm, Nicole, Weiss, William A, Qi, Jun, Beroukhim, Rameen, Piccioni, Federica, Johannessen, Cory, and Stegmaier, Kimberly

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Human Genome, Cancer, Cancer Genomics, 5.1 Pharmaceuticals, Animals, Azepines, Cell Line, Tumor, Disease-Free Survival, Drug Resistance, Neoplasm, Epigenesis, Genetic, Female, Humans, Indazoles, Mice, Nude, Molecular Targeted Therapy, Neuroblastoma, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Proteins, Signal Transduction, Sulfonamides, Triazoles, Xenograft Model Antitumor Assays, BET inhibition, MYCN, PI3K signaling, drug resistance, enhancer remodeling, neuroblastoma, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Drug resistance represents a major challenge to achieving durable responses to cancer therapeutics. Resistance mechanisms to epigenetically targeted drugs remain largely unexplored. We used bromodomain and extra-terminal domain (BET) inhibition in neuroblastoma as a prototype to model resistance to chromatin modulatory therapeutics. Genome-scale, pooled lentiviral open reading frame (ORF) and CRISPR knockout rescue screens nominated the phosphatidylinositol 3-kinase (PI3K) pathway as promoting resistance to BET inhibition. Transcriptomic and chromatin profiling of resistant cells revealed that global enhancer remodeling is associated with upregulation of receptor tyrosine kinases (RTKs), activation of PI3K signaling, and vulnerability to RTK/PI3K inhibition. Large-scale combinatorial screening with BET inhibitors identified PI3K inhibitors among the most synergistic upfront combinations. These studies provide a roadmap to elucidate resistance to epigenetic-targeted therapeutics and inform efficacious combination therapies.

Published
2018

2. CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2

Author

Chen, Liying, Alexe, Gabriela, Dharia, Neekesh V, Ross, Linda, Iniguez, Amanda Balboni, Conway, Amy Saur, Wang, Emily Jue, Veschi, Veronica, Lam, Norris, Qi, Jun, Gustafson, W Clay, Nasholm, Nicole, Vazquez, Francisca, Weir, Barbara A, Cowley, Glenn S, Ali, Levi D, Pantel, Sasha, Jiang, Guozhi, Harrington, William F, Lee, Yenarae, Goodale, Amy, Lubonja, Rakela, Krill-Burger, John M, Meyers, Robin M, Tsherniak, Aviad, Root, David E, Bradner, James E, Golub, Todd R, Roberts, Charles WM, Hahn, William C, Weiss, William A, Thiele, Carol J, and Stegmaier, Kimberly

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Neuroblastoma, Cancer, Cancer Genomics, Human Genome, Orphan Drug, Pediatric Cancer, Neurosciences, Pediatric, Rare Diseases, Genetics, 5.1 Pharmaceuticals, CRISPR-Cas Systems, Cell Differentiation, Cell Line, Tumor, Enhancer of Zeste Homolog 2 Protein, Gene Amplification, Gene Expression Regulation, Neoplastic, Humans, N-Myc Proto-Oncogene Protein, Neurons, Up-Regulation, Epigenetics, Oncology, Medical and Health Sciences, Immunology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Pharmacologically difficult targets, such as MYC transcription factors, represent a major challenge in cancer therapy. For the childhood cancer neuroblastoma, amplification of the oncogene MYCN is associated with high-risk disease and poor prognosis. Here, we deployed genome-scale CRISPR-Cas9 screening of MYCN-amplified neuroblastoma and found a preferential dependency on genes encoding the polycomb repressive complex 2 (PRC2) components EZH2, EED, and SUZ12. Genetic and pharmacological suppression of EZH2 inhibited neuroblastoma growth in vitro and in vivo. Moreover, compared with neuroblastomas without MYCN amplification, MYCN-amplified neuroblastomas expressed higher levels of EZH2. ChIP analysis showed that MYCN binds at the EZH2 promoter, thereby directly driving expression. Transcriptomic and epigenetic analysis, as well as genetic rescue experiments, revealed that EZH2 represses neuronal differentiation in neuroblastoma in a PRC2-dependent manner. Moreover, MYCN-amplified and high-risk primary tumors from patients with neuroblastoma exhibited strong repression of EZH2-regulated genes. Additionally, overexpression of IGFBP3, a direct EZH2 target, suppressed neuroblastoma growth in vitro and in vivo. We further observed strong synergy between histone deacetylase inhibitors and EZH2 inhibitors. Together, these observations demonstrate that MYCN upregulates EZH2, leading to inactivation of a tumor suppressor program in neuroblastoma, and support testing EZH2 inhibitors in patients with MYCN-amplified neuroblastoma.

Published
2018

3. High-throughput Phenotyping of Lung Cancer Somatic Mutations

Author

Berger, Alice H, Brooks, Angela N, Wu, Xiaoyun, Shrestha, Yashaswi, Chouinard, Candace, Piccioni, Federica, Bagul, Mukta, Kamburov, Atanas, Imielinski, Marcin, Hogstrom, Larson, Zhu, Cong, Yang, Xiaoping, Pantel, Sasha, Sakai, Ryo, Watson, Jacqueline, Kaplan, Nathan, Campbell, Joshua D, Singh, Shantanu, Root, David E, Narayan, Rajiv, Natoli, Ted, Lahr, David L, Tirosh, Itay, Tamayo, Pablo, Getz, Gad, Wong, Bang, Doench, John, Subramanian, Aravind, Golub, Todd R, Meyerson, Matthew, and Boehm, Jesse S

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Bioinformatics and Computational Biology, Genetics, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Lung, Human Genome, Cancer Genomics, Biotechnology, Lung Cancer, 2.1 Biological and endogenous factors, Adenocarcinoma, Adenocarcinoma of Lung, Animals, Cell Line, Tumor, Gene Expression Profiling, Heterografts, High-Throughput Nucleotide Sequencing, Humans, Lung Neoplasms, Mice, Mutation, Oncogenes, Phenotype, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Recent genome sequencing efforts have identified millions of somatic mutations in cancer. However, the functional impact of most variants is poorly understood. Here we characterize 194 somatic mutations identified in primary lung adenocarcinomas. We present an expression-based variant-impact phenotyping (eVIP) method that uses gene expression changes to distinguish impactful from neutral somatic mutations. eVIP identified 69% of mutations analyzed as impactful and 31% as functionally neutral. A subset of the impactful mutations induces xenograft tumor formation in mice and/or confers resistance to cellular EGFR inhibition. Among these impactful variants are rare somatic, clinically actionable variants including EGFR S645C, ARAF S214C and S214F, ERBB2 S418T, and multiple BRAF variants, demonstrating that rare mutations can be functionally important in cancer.

Published
2016

4. Defining a Cancer Dependency Map

Author

Tsherniak, Aviad, Vazquez, Francisca, Montgomery, Phil G., Weir, Barbara A., Kryukov, Gregory, Cowley, Glenn S., Gill, Stanley, Harrington, William F., Pantel, Sasha, Krill-Burger, John M., Meyers, Robin M., Ali, Levi, Goodale, Amy, Lee, Yenarae, Jiang, Guozhi, Hsiao, Jessica, Gerath, William F.J., Howell, Sara, Merkel, Erin, Ghandi, Mahmoud, Garraway, Levi A., Root, David E., Golub, Todd R., Boehm, Jesse S., and Hahn, William C.

Published
2017
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6. Agreement between two large pan-cancer CRISPR-Cas9 gene dependency data sets

Author

Dempster, Joshua M., Pacini, Clare, Pantel, Sasha, Behan, Fiona M., Green, Thomas, Krill-Burger, John, Beaver, Charlotte M., Younger, Scott T., Zhivich, Victor, Najgebauer, Hanna, Allen, Felicity, Gonçalves, Emanuel, Shepherd, Rebecca, Doench, John G., Yusa, Kosuke, Vazquez, Francisca, Parts, Leopold, Boehm, Jesse S., Golub, Todd R., Hahn, William C., Root, David E., Garnett, Mathew J., Tsherniak, Aviad, and Iorio, Francesco

Published
2019
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7. Supplementary Table S4 from Pooled Genomic Screens Identify Anti-apoptotic Genes as Targetable Mediators of Chemotherapy Resistance in Ovarian Cancer

Author

Stover, Elizabeth H., primary, Baco, Maria B., primary, Cohen, Ofir, primary, Li, Yvonne Y., primary, Christie, Elizabeth L., primary, Bagul, Mukta, primary, Goodale, Amy, primary, Lee, Yenarae, primary, Pantel, Sasha, primary, Rees, Matthew G., primary, Wei, Guo, primary, Presser, Adam G., primary, Gelbard, Maya K., primary, Zhang, Weiqun, primary, Zervantonakis, Ioannis K., primary, Bhola, Patrick D., primary, Ryan, Jeremy, primary, Guerriero, Jennifer L., primary, Montero, Joan, primary, Liang, Felice J., primary, Cherniack, Andrew D., primary, Piccioni, Federica, primary, Matulonis, Ursula A., primary, Bowtell, David D.L., primary, Sarosiek, Kristopher A., primary, Letai, Anthony, primary, Garraway, Levi A., primary, Johannessen, Cory M., primary, and Meyerson, Matthew, primary

Published
2023
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8. Supplementary Figures S6 - S10 from Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting

Author

Aguirre, Andrew J., primary, Meyers, Robin M., primary, Weir, Barbara A., primary, Vazquez, Francisca, primary, Zhang, Cheng-Zhong, primary, Ben-David, Uri, primary, Cook, April, primary, Ha, Gavin, primary, Harrington, William F., primary, Doshi, Mihir B., primary, Kost-Alimova, Maria, primary, Gill, Stanley, primary, Xu, Han, primary, Ali, Levi D., primary, Jiang, Guozhi, primary, Pantel, Sasha, primary, Lee, Yenarae, primary, Goodale, Amy, primary, Cherniack, Andrew D., primary, Oh, Coyin, primary, Kryukov, Gregory, primary, Cowley, Glenn S., primary, Garraway, Levi A., primary, Stegmaier, Kimberly, primary, Roberts, Charles W., primary, Golub, Todd R., primary, Meyerson, Matthew, primary, Root, David E., primary, Tsherniak, Aviad, primary, and Hahn, William C., primary

Published
2023
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9. Data from Pooled Genomic Screens Identify Anti-apoptotic Genes as Targetable Mediators of Chemotherapy Resistance in Ovarian Cancer

Author

Stover, Elizabeth H., primary, Baco, Maria B., primary, Cohen, Ofir, primary, Li, Yvonne Y., primary, Christie, Elizabeth L., primary, Bagul, Mukta, primary, Goodale, Amy, primary, Lee, Yenarae, primary, Pantel, Sasha, primary, Rees, Matthew G., primary, Wei, Guo, primary, Presser, Adam G., primary, Gelbard, Maya K., primary, Zhang, Weiqun, primary, Zervantonakis, Ioannis K., primary, Bhola, Patrick D., primary, Ryan, Jeremy, primary, Guerriero, Jennifer L., primary, Montero, Joan, primary, Liang, Felice J., primary, Cherniack, Andrew D., primary, Piccioni, Federica, primary, Matulonis, Ursula A., primary, Bowtell, David D.L., primary, Sarosiek, Kristopher A., primary, Letai, Anthony, primary, Garraway, Levi A., primary, Johannessen, Cory M., primary, and Meyerson, Matthew, primary

Published
2023
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10. Supplementary Table S1 from Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting

Author

Aguirre, Andrew J., primary, Meyers, Robin M., primary, Weir, Barbara A., primary, Vazquez, Francisca, primary, Zhang, Cheng-Zhong, primary, Ben-David, Uri, primary, Cook, April, primary, Ha, Gavin, primary, Harrington, William F., primary, Doshi, Mihir B., primary, Kost-Alimova, Maria, primary, Gill, Stanley, primary, Xu, Han, primary, Ali, Levi D., primary, Jiang, Guozhi, primary, Pantel, Sasha, primary, Lee, Yenarae, primary, Goodale, Amy, primary, Cherniack, Andrew D., primary, Oh, Coyin, primary, Kryukov, Gregory, primary, Cowley, Glenn S., primary, Garraway, Levi A., primary, Stegmaier, Kimberly, primary, Roberts, Charles W., primary, Golub, Todd R., primary, Meyerson, Matthew, primary, Root, David E., primary, Tsherniak, Aviad, primary, and Hahn, William C., primary

Published
2023
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11. Supplementary Figure Legends from Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting

Author

Aguirre, Andrew J., primary, Meyers, Robin M., primary, Weir, Barbara A., primary, Vazquez, Francisca, primary, Zhang, Cheng-Zhong, primary, Ben-David, Uri, primary, Cook, April, primary, Ha, Gavin, primary, Harrington, William F., primary, Doshi, Mihir B., primary, Kost-Alimova, Maria, primary, Gill, Stanley, primary, Xu, Han, primary, Ali, Levi D., primary, Jiang, Guozhi, primary, Pantel, Sasha, primary, Lee, Yenarae, primary, Goodale, Amy, primary, Cherniack, Andrew D., primary, Oh, Coyin, primary, Kryukov, Gregory, primary, Cowley, Glenn S., primary, Garraway, Levi A., primary, Stegmaier, Kimberly, primary, Roberts, Charles W., primary, Golub, Todd R., primary, Meyerson, Matthew, primary, Root, David E., primary, Tsherniak, Aviad, primary, and Hahn, William C., primary

Published
2023
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12. Data from Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting

Author

Aguirre, Andrew J., primary, Meyers, Robin M., primary, Weir, Barbara A., primary, Vazquez, Francisca, primary, Zhang, Cheng-Zhong, primary, Ben-David, Uri, primary, Cook, April, primary, Ha, Gavin, primary, Harrington, William F., primary, Doshi, Mihir B., primary, Kost-Alimova, Maria, primary, Gill, Stanley, primary, Xu, Han, primary, Ali, Levi D., primary, Jiang, Guozhi, primary, Pantel, Sasha, primary, Lee, Yenarae, primary, Goodale, Amy, primary, Cherniack, Andrew D., primary, Oh, Coyin, primary, Kryukov, Gregory, primary, Cowley, Glenn S., primary, Garraway, Levi A., primary, Stegmaier, Kimberly, primary, Roberts, Charles W., primary, Golub, Todd R., primary, Meyerson, Matthew, primary, Root, David E., primary, Tsherniak, Aviad, primary, and Hahn, William C., primary

Published
2023
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13. Supplementary figures and supplementary table legends from Pooled Genomic Screens Identify Anti-apoptotic Genes as Targetable Mediators of Chemotherapy Resistance in Ovarian Cancer

Author

Stover, Elizabeth H., primary, Baco, Maria B., primary, Cohen, Ofir, primary, Li, Yvonne Y., primary, Christie, Elizabeth L., primary, Bagul, Mukta, primary, Goodale, Amy, primary, Lee, Yenarae, primary, Pantel, Sasha, primary, Rees, Matthew G., primary, Wei, Guo, primary, Presser, Adam G., primary, Gelbard, Maya K., primary, Zhang, Weiqun, primary, Zervantonakis, Ioannis K., primary, Bhola, Patrick D., primary, Ryan, Jeremy, primary, Guerriero, Jennifer L., primary, Montero, Joan, primary, Liang, Felice J., primary, Cherniack, Andrew D., primary, Piccioni, Federica, primary, Matulonis, Ursula A., primary, Bowtell, David D.L., primary, Sarosiek, Kristopher A., primary, Letai, Anthony, primary, Garraway, Levi A., primary, Johannessen, Cory M., primary, and Meyerson, Matthew, primary

Published
2023
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14. Supplementary methods from Pooled Genomic Screens Identify Anti-apoptotic Genes as Targetable Mediators of Chemotherapy Resistance in Ovarian Cancer

Author

Stover, Elizabeth H., primary, Baco, Maria B., primary, Cohen, Ofir, primary, Li, Yvonne Y., primary, Christie, Elizabeth L., primary, Bagul, Mukta, primary, Goodale, Amy, primary, Lee, Yenarae, primary, Pantel, Sasha, primary, Rees, Matthew G., primary, Wei, Guo, primary, Presser, Adam G., primary, Gelbard, Maya K., primary, Zhang, Weiqun, primary, Zervantonakis, Ioannis K., primary, Bhola, Patrick D., primary, Ryan, Jeremy, primary, Guerriero, Jennifer L., primary, Montero, Joan, primary, Liang, Felice J., primary, Cherniack, Andrew D., primary, Piccioni, Federica, primary, Matulonis, Ursula A., primary, Bowtell, David D.L., primary, Sarosiek, Kristopher A., primary, Letai, Anthony, primary, Garraway, Levi A., primary, Johannessen, Cory M., primary, and Meyerson, Matthew, primary

Published
2023
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15. Supplementary Methods from Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting

Author

Aguirre, Andrew J., primary, Meyers, Robin M., primary, Weir, Barbara A., primary, Vazquez, Francisca, primary, Zhang, Cheng-Zhong, primary, Ben-David, Uri, primary, Cook, April, primary, Ha, Gavin, primary, Harrington, William F., primary, Doshi, Mihir B., primary, Kost-Alimova, Maria, primary, Gill, Stanley, primary, Xu, Han, primary, Ali, Levi D., primary, Jiang, Guozhi, primary, Pantel, Sasha, primary, Lee, Yenarae, primary, Goodale, Amy, primary, Cherniack, Andrew D., primary, Oh, Coyin, primary, Kryukov, Gregory, primary, Cowley, Glenn S., primary, Garraway, Levi A., primary, Stegmaier, Kimberly, primary, Roberts, Charles W., primary, Golub, Todd R., primary, Meyerson, Matthew, primary, Root, David E., primary, Tsherniak, Aviad, primary, and Hahn, William C., primary

Published
2023
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18. Cas9 activates the p53 pathway and selects for p53-inactivating mutations

Author

Enache, Oana M., primary, Rendo, Veronica, additional, Abdusamad, Mai, additional, Lam, Daniel, additional, Davison, Desiree, additional, Pal, Sangita, additional, Currimjee, Naomi, additional, Hess, Julian, additional, Pantel, Sasha, additional, Nag, Anwesha, additional, Thorner, Aaron R., additional, Doench, John G., additional, Vazquez, Francisca, additional, Beroukhim, Rameen, additional, Golub, Todd R., additional, and Ben-David, Uri, additional

Published
2020
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19. Abstract AP14: POOLED GENOMIC SCREENS IDENTIFY ANTI-APOPTOTIC GENES AS MEDIATORS OF CHEMOTHERAPY RESISTANCE IN OVARIAN CANCER

Author

Stover, Elizabeth H., primary, Baco, Maria B., additional, Cohen, Ofir, additional, Li, Yvonne, additional, Christie, Elizabeth, additional, Bagul, Mukta, additional, Goodale, Amy, additional, Lee, Yenarae, additional, Pantel, Sasha, additional, Rees, Matthew, additional, Wei, Guo, additional, Presser, Adam, additional, Zervantonakis, Ioannis, additional, Bhola, Patrick, additional, Ryan, Jeremy, additional, Guerriero, Jennifer, additional, Liang, Felice, additional, Cherniack, Andrew, additional, Piccioni, Federica, additional, Matulonis, Ursula A., additional, Bowtell, David D. L., additional, Letai, Anthony, additional, Sarosiek, Kris, additional, Garraway, Levi, additional, Johannessen, Cory M., additional, and Meyerson, Matthew, additional

Published
2019
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20. Pooled Genomic Screens Identify Anti-apoptotic Genes as Targetable Mediators of Chemotherapy Resistance in Ovarian Cancer

Author

Stover, Elizabeth H., primary, Baco, Maria B., additional, Cohen, Ofir, additional, Li, Yvonne Y., additional, Christie, Elizabeth L., additional, Bagul, Mukta, additional, Goodale, Amy, additional, Lee, Yenarae, additional, Pantel, Sasha, additional, Rees, Matthew G., additional, Wei, Guo, additional, Presser, Adam G., additional, Gelbard, Maya K., additional, Zhang, Weiqun, additional, Zervantonakis, Ioannis K., additional, Bhola, Patrick D., additional, Ryan, Jeremy, additional, Guerriero, Jennifer L., additional, Montero, Joan, additional, Liang, Felice J., additional, Cherniack, Andrew D., additional, Piccioni, Federica, additional, Matulonis, Ursula A., additional, Bowtell, David D.L., additional, Sarosiek, Kristopher A., additional, Letai, Anthony, additional, Garraway, Levi A., additional, Johannessen, Cory M., additional, and Meyerson, Matthew, additional

Published
2019
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22. Agreement between two large pan-cancer CRISPR-Cas9 gene dependency datasets

Author

Dempster, Joshua M., primary, Pacini, Clare, additional, Pantel, Sasha, additional, Behan, Fiona M., additional, Green, Thomas, additional, Krill-Burger, John, additional, Beaver, Charlotte M., additional, Younger, Scott T., additional, Zhivich, Victor, additional, Najgebauer, Hanna, additional, Allen, Felicity, additional, Gonçalves, Emanuel, additional, Shepherd, Rebecca, additional, Doench, John G., additional, Yusa, Kosuke, additional, Vazquez, Francisca, additional, Parts, Leopold, additional, Boehm, Jesse S., additional, Golub, Todd R., additional, Hahn, William C., additional, Root, David E., additional, Garnett, Mathew J., additional, Iorio, Francesco, additional, and Tsherniak, Aviad, additional

Published
2019
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23. Abstract 1815: Massively parallel identification of conserved drug resistant mutations in kinases

Author

Persky, Nicole S., primary, Hernandez, Desiree, additional, Cordova, Jonathon, additional, Walker, Amanda, additional, Brenan, Lisa, additional, Piccioni, Federica, additional, Pantel, Sasha, additional, Lee, Yenarae, additional, Goodale, Amy, additional, Yang, Xiaoping, additional, Mitsuishi, Yoichiro, additional, Carmo, Mariana Do, additional, Zhu, Cong, additional, Andreev, Aleksandr, additional, Root, David E., additional, and Johannessen, Cory M., additional

Published
2018
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24. CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2

Author

Chen, Liying, primary, Alexe, Gabriela, additional, Dharia, Neekesh V., additional, Ross, Linda, additional, Iniguez, Amanda Balboni, additional, Conway, Amy Saur, additional, Wang, Emily Jue, additional, Veschi, Veronica, additional, Lam, Norris, additional, Qi, Jun, additional, Gustafson, W. Clay, additional, Nasholm, Nicole, additional, Vazquez, Francisca, additional, Weir, Barbara A., additional, Cowley, Glenn S., additional, Ali, Levi D., additional, Pantel, Sasha, additional, Jiang, Guozhi, additional, Harrington, William F., additional, Lee, Yenarae, additional, Goodale, Amy, additional, Lubonja, Rakela, additional, Krill-Burger, John M., additional, Meyers, Robin M., additional, Tsherniak, Aviad, additional, Root, David E., additional, Bradner, James E., additional, Golub, Todd R., additional, Roberts, Charles W.M., additional, Hahn, William C., additional, Weiss, William A., additional, Thiele, Carol J., additional, and Stegmaier, Kimberly, additional

Published
2017
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25. High-throughput Phenotyping of Lung Cancer Somatic Mutations

Author

Berger, Alice H., primary, Brooks, Angela N., additional, Wu, Xiaoyun, additional, Shrestha, Yashaswi, additional, Chouinard, Candace, additional, Piccioni, Federica, additional, Bagul, Mukta, additional, Kamburov, Atanas, additional, Imielinski, Marcin, additional, Hogstrom, Larson, additional, Zhu, Cong, additional, Yang, Xiaoping, additional, Pantel, Sasha, additional, Sakai, Ryo, additional, Watson, Jacqueline, additional, Kaplan, Nathan, additional, Campbell, Joshua D., additional, Singh, Shantanu, additional, Root, David E., additional, Narayan, Rajiv, additional, Natoli, Ted, additional, Lahr, David L., additional, Tirosh, Itay, additional, Tamayo, Pablo, additional, Getz, Gad, additional, Wong, Bang, additional, Doench, John, additional, Subramanian, Aravind, additional, Golub, Todd R., additional, Meyerson, Matthew, additional, and Boehm, Jesse S., additional

Published
2017
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26. Computational correction of copy number effect improves specificity of CRISPR–Cas9 essentiality screens in cancer cells

Author

Meyers, Robin M, primary, Bryan, Jordan G, additional, McFarland, James M, additional, Weir, Barbara A, additional, Sizemore, Ann E, additional, Xu, Han, additional, Dharia, Neekesh V, additional, Montgomery, Phillip G, additional, Cowley, Glenn S, additional, Pantel, Sasha, additional, Goodale, Amy, additional, Lee, Yenarae, additional, Ali, Levi D, additional, Jiang, Guozhi, additional, Lubonja, Rakela, additional, Harrington, William F, additional, Strickland, Matthew, additional, Wu, Ting, additional, Hawes, Derek C, additional, Zhivich, Victor A, additional, Wyatt, Meghan R, additional, Kalani, Zohra, additional, Chang, Jaime J, additional, Okamoto, Michael, additional, Stegmaier, Kimberly, additional, Golub, Todd R, additional, Boehm, Jesse S, additional, Vazquez, Francisca, additional, Root, David E, additional, Hahn, William C, additional, and Tsherniak, Aviad, additional

Published
2017
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27. Computational correction of copy-number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells

Author

Meyers, Robin M., primary, Bryan, Jordan G., additional, McFarland, James M., additional, Weir, Barbara A., additional, Sizemore, Ann E., additional, Xu, Han, additional, Dharia, Neekesh V., additional, Montgomery, Phillip G., additional, Cowley, Glenn S., additional, Pantel, Sasha, additional, Goodale, Amy, additional, Lee, Yenarae, additional, Ali, Levi D., additional, Jiang, Guozhi, additional, Lubonja, Rakela, additional, Harrington, William F., additional, Strickland, Matthew, additional, Wu, Ting, additional, Hawes, Derek C., additional, Zhivich, Victor A., additional, Wyatt, Meghan R., additional, Kalani, Zohra, additional, Chang, Jaime J., additional, Okamoto, Michael, additional, Golub, Todd R., additional, Boehm, Jesse S., additional, Vazquez, Francisca, additional, Root, David E., additional, Hahn, William C., additional, and Tsherniak, Aviad, additional

Published
2017
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28. TRTH-15. RESISTANCE MECHANISMS TO BET-BROMODOMAIN INHIBITION IN MYC-AMPLIFIED MEDULLOBLASTOMA

Author

Bandopadhayay, Pratiti, primary, Paolella, Brenton, additional, O’Rourke, Ryan, additional, Ho, Patricia, additional, Greenwald, Noah, additional, Sharpira, Ofer, additional, Pantel, Sasha, additional, Bagul, Mukta, additional, Tracy, Adam, additional, Roti, Giovanni, additional, Balboni, Amanda, additional, Vazquez, Francisca, additional, Ligon, Keith, additional, Piccioni, Federica, additional, Stegmaier, Kimberly, additional, Johannessen, Cory, additional, and Beroukhim, Rameen, additional

Published
2017
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29. Abstract B39: Genomic copy number alterations introduce a gene-independent viability bias in CRISPR-Cas9 knock-out screens of cancer cell lines

Author

Meyers, Robin M., primary, Aguirre, Andrew J., additional, Weir, Barbara A., additional, Vazquez, Francisca, additional, Zhang, Cheng-Zhong, additional, Ben-David, Uri, additional, Cook, April, additional, Ha, Gavin, additional, Harrington, William F., additional, Doshi, Mihir, additional, Gill, Stanley, additional, Xu, Han, additional, Ali, Levi D., additional, Jiang, Guozhi, additional, Pantel, Sasha, additional, Lee, Yenarae, additional, Goodale, Amy, additional, Cherniack, Andrew D., additional, Oh, Coyin, additional, Kryukov, Gregory, additional, Cowley, Glenn S., additional, Garraway, Levi A., additional, Stegmaier, Kimberly, additional, Roberts, Charles W., additional, Golub, Todd R., additional, Meyerson, Matthew, additional, Root, David E., additional, Tsherniak, Aviad, additional, and Hahn, William C., additional

Published
2017
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30. Abstract PR02: Towards a Cancer Dependency Map

Author

Tsherniak, Aviad, primary, Vazquez, Francisca, additional, Weir, Barbara, additional, Montgomery, Philip, additional, Cowley, Glenn, additional, Gill, Stanley, additional, Kryukov, Gregory, additional, Pantel, Sasha, additional, Harrington, Will, additional, Burger, Mike, additional, Meyers, Robin, additional, Ali, Levi, additional, Goodale, Amy, additional, Lee, Yenarae, additional, Garraway, Levi, additional, Boehm, Jesse, additional, Root, David, additional, Golub, Todd, additional, and Hahn, William, additional

Published
2017
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31. Abstract B43: Towards a Cancer Dependency Map

Author

Tsherniak, Aviad, primary, Vazquez, Francisca, additional, Weir, Barbara, additional, Montgomery, Philip, additional, Cowley, Glenn, additional, Gill, Stanley, additional, Kryukov, Gregory, additional, Pantel, Sasha, additional, Harrington, Will, additional, Burger, Mike, additional, Meyers, Robin, additional, Ali, Levi, additional, Goodale, Amy, additional, Lee, Yenarae, additional, Garraway, Levi, additional, Boehm, Jesse, additional, Root, David, additional, Golub, Todd, additional, and Hahn, William, additional

Published
2017
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32. Abstract B44: Emerging targets from Cancer Dependency Map v0.1

Author

Vazquez, Francisca, primary, Tsherniak, Aviad, additional, Weir, Barbara, additional, Montgomery, Phil, additional, Cowley, Glenn, additional, Gill, Stanley, additional, Kryukov, Gregory, additional, Pantel, Sasha, additional, Harrington, Will, additional, Burger, Mike, additional, Meyers, Robin, additional, Ali, Levi, additional, Goodale, Amy, additional, Lee, Yenarae, additional, Garraway, Levi, additional, Boehm, Jesse, additional, Root, David, additional, Golub, Todd, additional, and Hahn, William, additional

Published
2017
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33. Phenotypic Characterization of a Comprehensive Set of MAPK1 /ERK2 Missense Mutants

Author

Brenan, Lisa, primary, Andreev, Aleksandr, additional, Cohen, Ofir, additional, Pantel, Sasha, additional, Kamburov, Atanas, additional, Cacchiarelli, Davide, additional, Persky, Nicole S., additional, Zhu, Cong, additional, Bagul, Mukta, additional, Goetz, Eva M., additional, Burgin, Alex B., additional, Garraway, Levi A., additional, Getz, Gad, additional, Mikkelsen, Tarjei S., additional, Piccioni, Federica, additional, Root, David E., additional, and Johannessen, Cory M., additional

Published
2016
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34. Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting

Author

Aguirre, Andrew J., primary, Meyers, Robin M., additional, Weir, Barbara A., additional, Vazquez, Francisca, additional, Zhang, Cheng-Zhong, additional, Ben-David, Uri, additional, Cook, April, additional, Ha, Gavin, additional, Harrington, William F., additional, Doshi, Mihir B., additional, Kost-Alimova, Maria, additional, Gill, Stanley, additional, Xu, Han, additional, Ali, Levi D., additional, Jiang, Guozhi, additional, Pantel, Sasha, additional, Lee, Yenarae, additional, Goodale, Amy, additional, Cherniack, Andrew D., additional, Oh, Coyin, additional, Kryukov, Gregory, additional, Cowley, Glenn S., additional, Garraway, Levi A., additional, Stegmaier, Kimberly, additional, Roberts, Charles W., additional, Golub, Todd R., additional, Meyerson, Matthew, additional, Root, David E., additional, Tsherniak, Aviad, additional, and Hahn, William C., additional

Published
2016
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35. Abstract 4368: High-throughput phenotyping of lung cancer somatic mutations

Author

Berger, Alice H., primary, Brooks, Angela N., additional, Wu, Xiaoyun, additional, Shrestha, Yashaswi, additional, Chouinard, Candace, additional, Piccioni, Federica, additional, Bagul, Mukta, additional, Kamburov, Atanas, additional, Imielinski, Marcin, additional, Hogstrom, Larson, additional, Zhu, Cong, additional, Yang, Xiaoping, additional, Pantel, Sasha, additional, Sakai, Ryo, additional, Kaplan, Nathan, additional, Root, David, additional, Narayan, Rajiv, additional, Natoli, Ted, additional, Lahr, David, additional, Tirosh, Itay, additional, Tamayo, Pablo, additional, Getz, Gad, additional, Wong, Bang, additional, Doench, John, additional, Subramanian, Aravind, additional, Golub, Todd R., additional, Meyerson, Matthew, additional, and Boehm, Jesse S., additional

Published
2016
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36. Phenotypic Characterization of a Comprehensive Set of MAPK1/ERK2 Missense Mutants.

Author

Brenan, Lisa, Andreev, Aleksandr, Cohen, Ofir, Pantel, Sasha, Kamburov, Atanas, Cacchiarelli, Davide, Persky, Nicole S., Zhu, Cong, Bagul, Mukta, Goetz, Eva M., Burgin, Alex B., Garraway, Levi A., Getz, Gad, Mikkelsen, Tarjei S., Piccioni, Federica, Root, David E., and Johannessen, Cory M.

Abstract

Summary Tumor-specific genomic information has the potential to guide therapeutic strategies and revolutionize patient treatment. Currently, this approach is limited by an abundance of disease-associated mutants whose biological functions and impacts on therapeutic response are uncharacterized. To begin to address this limitation, we functionally characterized nearly all (99.84%) missense mutants of MAPK1 /ERK2, an essential effector of oncogenic RAS and RAF. Using this approach, we discovered rare gain- and loss-of-function ERK2 mutants found in human tumors, revealing that, in the context of this assay, mutational frequency alone cannot identify all functionally impactful mutants. Gain-of-function ERK2 mutants induced variable responses to RAF-, MEK-, and ERK-directed therapies, providing a reference for future treatment decisions. Tumor-associated mutations spatially clustered in two ERK2 effector-recruitment domains yet produced mutants with opposite phenotypes. This approach articulates an allele-characterization framework that can be scaled to meet the goals of genome-guided oncology. [ABSTRACT FROM AUTHOR]

Published
2016
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37. Computational correction of copy-number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells

Author

Meyers, Robin M., Bryan, Jordan G., McFarland, James M., Weir, Barbara A., Sizemore, Ann E., Xu, Han, Dharia, Neekesh V., Montgomery, Phillip G., Cowley, Glenn S., Pantel, Sasha, Goodale, Amy, Lee, Yenarae, Ali, Levi D., Jiang, Guozhi, Lubonja, Rakela, Harrington, William F., Strickland, Matthew, Wu, Ting, Hawes, Derek C., Zhivich, Victor A., Wyatt, Meghan R., Kalani, Zohra, Chang, Jaime J., Okamoto, Michael, Stegmaier, Kimberly, Golub, Todd R., Boehm, Jesse S., Vazquez, Francisca, Root, David E., Hahn, William C., and Tsherniak, Aviad

Abstract

The CRISPR-Cas9 system has revolutionized gene editing both on single genes and in multiplexed loss-of-function screens, enabling precise genome-scale identification of genes essential to proliferation and survival of cancer cells1,2. However, previous studies reported that a gene-independent anti-proliferative effect of Cas9-mediated DNA cleavage confounds such measurement of genetic dependency, leading to false positive results in copy number amplified regions3,4. We developed CERES, a computational method to estimate gene dependency levels from CRISPR-Cas9 essentiality screens while accounting for the copy-number-specific effect. As part of our efforts to define a cancer dependency map, we performed genome-scale CRISPR-Cas9 essentiality screens across 342 cancer cell lines and applied CERES to this dataset. We found that CERES reduced false positive results and estimated sgRNA activity for both this dataset and previously published screens performed with different sgRNA libraries. Here, we demonstrate the utility of this collection of screens, upon CERES correction, in revealing cancer-type-specific vulnerabilities.

Published
2017
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38. Agreement between two large pan-cancer CRISPR-Cas9 gene dependency data sets

Author

Dempster, Joshua M, Pacini, Clare, Pantel, Sasha, Behan, Fiona M, Green, Thomas, Krill-Burger, John, Beaver, Charlotte M, Younger, Scott T, Zhivich, Victor, Najgebauer, Hanna, Allen, Felicity, Gonçalves, Emanuel, Shepherd, Rebecca, Doench, John G, Yusa, Kosuke, Vazquez, Francisca, Parts, Leopold, Boehm, Jesse S, Golub, Todd R, Hahn, William C, Root, David E, Garnett, Mathew J, Tsherniak, Aviad, and Iorio, Francesco

Subjects
Genes, Essential, Gene Expression Profiling, Datasets as Topic, Reproducibility of Results, Antineoplastic Agents, Genomics, Oncogenes, 3. Good health, Small Molecule Libraries, Cell Line, Tumor, Neoplasms, Biomarkers, Tumor, Humans, Molecular Targeted Therapy, CRISPR-Cas Systems, Drug Screening Assays, Antitumor, Precision Medicine
Abstract

Genome-scale CRISPR-Cas9 viability screens performed in cancer cell lines provide a systematic approach to identify cancer dependencies and new therapeutic targets. As multiple large-scale screens become available, a formal assessment of the reproducibility of these experiments becomes necessary. We analyze data from recently published pan-cancer CRISPR-Cas9 screens performed at the Broad and Sanger Institutes. Despite significant differences in experimental protocols and reagents, we find that the screen results are highly concordant across multiple metrics with both common and specific dependencies jointly identified across the two studies. Furthermore, robust biomarkers of gene dependency found in one data set are recovered in the other. Through further analysis and replication experiments at each institute, we show that batch effects are driven principally by two key experimental parameters: the reagent library and the assay length. These results indicate that the Broad and Sanger CRISPR-Cas9 viability screens yield robust and reproducible findings.

39. CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2.

Author

Liying Chen, Alexe, Gabriela, Dharia, Neekesh V., Ross, Linda, Iniguez, Amanda Balboni, Conway, Amy Saur, Emily Jue Wang, Veschi, Veronica, Lam, Norris, Jun Qi, Gustafson, W. Clay, Nasholm, Nicole, Vazquez, Francisca, Weir, Barbara A., Cowley, Glenn S., Ali, Levi D., Pantel, Sasha, Guozhi Jiang, Harrington, William F., and Yenarae Lee

Subjects
*NEUROBLASTOMA, *TRANSCRIPTION factors, *CANCER treatment, *GENE expression, *LEUKEMIA, *BIOCHEMISTRY, *CELL differentiation, *CELL lines, *COMPARATIVE studies, *GENE amplification, *GENES, *PHENOMENOLOGY, *RESEARCH methodology, *MEDICAL cooperation, *NEURONS, *RESEARCH, *RESEARCH funding, *EVALUATION research
Abstract

Pharmacologically difficult targets, such as MYC transcription factors, represent a major challenge in cancer therapy. For the childhood cancer neuroblastoma, amplification of the oncogene MYCN is associated with high-risk disease and poor prognosis. Here, we deployed genome-scale CRISPR-Cas9 screening of MYCN-amplified neuroblastoma and found a preferential dependency on genes encoding the polycomb repressive complex 2 (PRC2) components EZH2, EED, and SUZ12. Genetic and pharmacological suppression of EZH2 inhibited neuroblastoma growth in vitro and in vivo. Moreover, compared with neuroblastomas without MYCN amplification, MYCN-amplified neuroblastomas expressed higher levels of EZH2. ChIP analysis showed that MYCN binds at the EZH2 promoter, thereby directly driving expression. Transcriptomic and epigenetic analysis, as well as genetic rescue experiments, revealed that EZH2 represses neuronal differentiation in neuroblastoma in a PRC2-dependent manner. Moreover, MYCN-amplified and high-risk primary tumors from patients with neuroblastoma exhibited strong repression of EZH2-regulated genes. Additionally, overexpression of IGFBP3, a direct EZH2 target, suppressed neuroblastoma growth in vitro and in vivo. We further observed strong synergy between histone deacetylase inhibitors and EZH2 inhibitors. Together, these observations demonstrate that MYCN upregulates EZH2, leading to inactivation of a tumor suppressor program in neuroblastoma, and support testing EZH2 inhibitors in patients with MYCN-amplified neuroblastoma. [ABSTRACT FROM AUTHOR]

Published
2018
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40. Phenotypic Characterization of a Comprehensive Set of MAPK1/ERK2 Missense Mutants

Author

Tarjei S. Mikkelsen, Federica Piccioni, Sasha Pantel, Nicole S. Persky, Eva M. Goetz, Cong Zhu, Alex B. Burgin, Levi A. Garraway, Mukta Bagul, Cory M. Johannessen, Gad Getz, Ofir Cohen, Davide Cacchiarelli, Aleksandr Andreev, Atanas Kamburov, Lisa Brenan, David E. Root, Brenan, Lisa, Andreev, Aleksandr, Cohen, Ofir, Pantel, Sasha, Kamburov, Atana, Cacchiarelli, Davide, Persky, Nicole S., Zhu, Cong, Bagul, Mukta, Goetz, Eva M., Burgin, Alex B., Garraway, Levi A., Getz, Gad, Mikkelsen, Tarjei S., Piccioni, Federica, Root, David E., and Johannessen, Cory M.

Subjects
0301 basic medicine, MAPK/ERK pathway, Models, Molecular, precision medicine, Mutant, Mutation, Missense, Protein Kinase Inhibitor, Reproducibility of Result, Context (language use), Biology, General Biochemistry, Genetics and Molecular Biology, Article, rare mutant, 03 medical and health sciences, Dual Specificity Phosphatase 6, Cell Line, Tumor, Missense mutation, Humans, cancer, Patient treatment, Phosphorylation, MAPK1, lcsh:QH301-705.5, Protein Kinase Inhibitors, Genetics, Mitogen-Activated Protein Kinase 1, Biochemistry, Genetics and Molecular Biology (all), Effector, Reproducibility of Results, rare mutants, Phenotype, functional biology, MAPK, ERK, 030104 developmental biology, lcsh:Biology (General), Drug Resistance, Neoplasm, precision oncology, Human
Abstract

SummaryTumor-specific genomic information has the potential to guide therapeutic strategies and revolutionize patient treatment. Currently, this approach is limited by an abundance of disease-associated mutants whose biological functions and impacts on therapeutic response are uncharacterized. To begin to address this limitation, we functionally characterized nearly all (99.84%) missense mutants of MAPK1/ERK2, an essential effector of oncogenic RAS and RAF. Using this approach, we discovered rare gain- and loss-of-function ERK2 mutants found in human tumors, revealing that, in the context of this assay, mutational frequency alone cannot identify all functionally impactful mutants. Gain-of-function ERK2 mutants induced variable responses to RAF-, MEK-, and ERK-directed therapies, providing a reference for future treatment decisions. Tumor-associated mutations spatially clustered in two ERK2 effector-recruitment domains yet produced mutants with opposite phenotypes. This approach articulates an allele-characterization framework that can be scaled to meet the goals of genome-guided oncology.

Published
2016

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