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1. IFITM proteins assist cellular uptake of diverse linked chemotypes

Author

Lou, Kevin, Wassarman, Douglas R, Yang, Tangpo, Paung, YiTing, Zhang, Ziyang, O'Loughlin, Thomas A, Moore, Megan K, Egan, Regina K, Greninger, Patricia, Benes, Cyril H, Seeliger, Markus A, Taunton, Jack, Gilbert, Luke A, and Shokat, Kevan M

Subjects
Biochemistry and Cell Biology, Medicinal and Biomolecular Chemistry, Chemical Sciences, Biological Sciences, Orphan Drug, Rare Diseases, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, General Science & Technology
Abstract

The search for cell-permeable drugs has conventionally focused on low-molecular weight (MW), nonpolar, rigid chemical structures. However, emerging therapeutic strategies break traditional drug design rules by employing flexibly linked chemical entities composed of more than one ligand. Using complementary genome-scale chemical-genetic approaches we identified an endogenous chemical uptake pathway involving interferon-induced transmembrane proteins (IFITMs) that modulates the cell permeability of a prototypical biopic inhibitor of MTOR (RapaLink-1, MW: 1784 g/mol). We devised additional linked inhibitors targeting BCR-ABL1 (DasatiLink-1, MW: 1518 g/mol) and EIF4A1 (BisRoc-1, MW: 1466 g/mol), uptake of which was facilitated by IFITMs. We also found that IFITMs moderately assisted some proteolysis-targeting chimeras and examined the physicochemical requirements for involvement of this uptake pathway.

Published
2022

2. A landscape of response to drug combinations in non-small cell lung cancer

Author

Nair, Nishanth Ulhas, Greninger, Patricia, Zhang, Xiaohu, Friedman, Adam A., Amzallag, Arnaud, Cortez, Eliane, Sahu, Avinash Das, Lee, Joo Sang, Dastur, Anahita, Egan, Regina K., Murchie, Ellen, Ceribelli, Michele, Crowther, Giovanna S., Beck, Erin, McClanaghan, Joseph, Klump-Thomas, Carleen, Boisvert, Jessica L., Damon, Leah J., Wilson, Kelli M., Ho, Jeffrey, Tam, Angela, McKnight, Crystal, Michael, Sam, Itkin, Zina, Garnett, Mathew J., Engelman, Jeffrey A., Haber, Daniel A., Thomas, Craig J., Ruppin, Eytan, and Benes, Cyril H.

Published
2023
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3. Differential Effector Engagement by Oncogenic KRAS

Author

Yuan, Tina L, Amzallag, Arnaud, Bagni, Rachel, Yi, Ming, Afghani, Shervin, Burgan, William, Fer, Nicole, Strathern, Leslie A, Powell, Katie, Smith, Brian, Waters, Andrew M, Drubin, David, Thomson, Ty, Liao, Rosy, Greninger, Patricia, Stein, Giovanna T, Murchie, Ellen, Cortez, Eliane, Egan, Regina K, Procter, Lauren, Bess, Matthew, Cheng, Kwong Tai, Lee, Chih-Shia, Lee, Liam Changwoo, Fellmann, Christof, Stephens, Robert, Luo, Ji, Lowe, Scott W, Benes, Cyril H, and McCormick, Frank

Subjects
Biochemistry and Cell Biology, Biological Sciences, Lung, Cancer, AMP-Activated Protein Kinase Kinases, Adenylate Kinase, Cell Line, Tumor, Drug Evaluation, Preclinical, Gene Expression Regulation, Neoplastic, Humans, Metabolic Networks and Pathways, Models, Biological, Mutation, Oncogenes, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins p21(ras), RNA Interference, RNA, Small Interfering, Small Molecule Libraries, KRAS, RNAi screen, RSK, paralogs, redundancy, Medical Physiology, Biological sciences
Abstract

KRAS can bind numerous effector proteins, which activate different downstream signaling events. The best known are RAF, phosphatidylinositide (PI)-3' kinase, and RalGDS families, but many additional direct and indirect effectors have been reported. We have assessed how these effectors contribute to several major phenotypes in a quantitative way, using an arrayed combinatorial siRNA screen in which we knocked down 41 KRAS effectors nodes in 92 cell lines. We show that every cell line has a unique combination of effector dependencies, but in spite of this heterogeneity, we were able to identify two major subtypes of KRAS mutant cancers of the lung, pancreas, and large intestine, which reflect different KRAS effector engagement and opportunities for therapeutic intervention.

Published
2018

5. Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma

Author

Saha, Supriya K, Gordan, John D, Kleinstiver, Benjamin P, Vu, Phuong, Najem, Mortada S, Yeo, Jia-Chi, Shi, Lei, Kato, Yasutaka, Levin, Rebecca S, Webber, James T, Damon, Leah J, Egan, Regina K, Greninger, Patricia, McDermott, Ultan, Garnett, Mathew J, Jenkins, Roger L, Rieger-Christ, Kimberly M, Sullivan, Travis B, Hezel, Aram F, Liss, Andrew S, Mizukami, Yusuke, Goyal, Lipika, Ferrone, Cristina R, Zhu, Andrew X, Joung, J Keith, Shokat, Kevan M, Benes, Cyril H, and Bardeesy, Nabeel

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Digestive Diseases - (Gallbladder), Cancer, Liver Disease, Orphan Drug, Liver Cancer, Digestive Diseases, Rare Diseases, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Animals, Bile Duct Neoplasms, Cell Line, Tumor, Cell Proliferation, Cholangiocarcinoma, Cluster Analysis, Dasatinib, Disease Models, Animal, Drug Resistance, Neoplasm, Gene Expression Profiling, Humans, Isocitrate Dehydrogenase, Mice, Mutation, Xenograft Model Antitumor Assays, src-Family Kinases, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

UnlabelledIntrahepatic cholangiocarcinoma (ICC) is an aggressive liver bile duct malignancy exhibiting frequent isocitrate dehydrogenase (IDH1/IDH2) mutations. Through a high-throughput drug screen of a large panel of cancer cell lines, including 17 biliary tract cancers, we found that IDH mutant (IDHm) ICC cells demonstrate a striking response to the multikinase inhibitor dasatinib, with the highest sensitivity among 682 solid tumor cell lines. Using unbiased proteomics to capture the activated kinome and CRISPR/Cas9-based genome editing to introduce dasatinib-resistant "gatekeeper" mutant kinases, we identified SRC as a critical dasatinib target in IDHm ICC. Importantly, dasatinib-treated IDHm xenografts exhibited pronounced apoptosis and tumor regression. Our results show that IDHm ICC cells have a unique dependency on SRC and suggest that dasatinib may have therapeutic benefit against IDHm ICC. Moreover, these proteomic and genome-editing strategies provide a systematic and broadly applicable approach to define targets of kinase inhibitors underlying drug responsiveness.SignificanceIDH mutations define a distinct subtype of ICC, a malignancy that is largely refractory to current therapies. Our work demonstrates that IDHm ICC cells are hypersensitive to dasatinib and critically dependent on SRC activity for survival and proliferation, pointing to new therapeutic strategies against these cancers. Cancer Discov; 6(7); 727-39. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 681.

Published
2016

6. Figure S5 from Pharmacologic Inhibition of SHP2 Blocks Both PI3K and MEK Signaling in Low-epiregulin HNSCC via GAB1

Author

Kurupi, Richard, primary, Floros, Konstantinos V., primary, Jacob, Sheeba, primary, Chawla, Ayesha T., primary, Cai, Jinyang, primary, Hu, Bin, primary, Puchalapalli, Madhavi, primary, Coon, Colin M., primary, Khatri, Rishabh, primary, Crowther, Giovanna Stein, primary, Egan, Regina K., primary, Murchie, Ellen, primary, Greninger, Patricia, primary, Dalton, Krista M., primary, Ghotra, Maninderjit S., primary, Boikos, Sosipatros A., primary, Koblinski, Jennifer E., primary, Harada, Hisashi, primary, Sun, Yue, primary, Morgan, Iain M., primary, Basu, Devraj, primary, Dozmorov, Mikhail G., primary, Benes, Cyril H., primary, and Faber, Anthony C., primary

Published
2023
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7. Table S1 from Pharmacologic Inhibition of SHP2 Blocks Both PI3K and MEK Signaling in Low-epiregulin HNSCC via GAB1

Author

Kurupi, Richard, primary, Floros, Konstantinos V., primary, Jacob, Sheeba, primary, Chawla, Ayesha T., primary, Cai, Jinyang, primary, Hu, Bin, primary, Puchalapalli, Madhavi, primary, Coon, Colin M., primary, Khatri, Rishabh, primary, Crowther, Giovanna Stein, primary, Egan, Regina K., primary, Murchie, Ellen, primary, Greninger, Patricia, primary, Dalton, Krista M., primary, Ghotra, Maninderjit S., primary, Boikos, Sosipatros A., primary, Koblinski, Jennifer E., primary, Harada, Hisashi, primary, Sun, Yue, primary, Morgan, Iain M., primary, Basu, Devraj, primary, Dozmorov, Mikhail G., primary, Benes, Cyril H., primary, and Faber, Anthony C., primary

Published
2023
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8. Data from Pharmacologic Inhibition of SHP2 Blocks Both PI3K and MEK Signaling in Low-epiregulin HNSCC via GAB1

Author

Kurupi, Richard, primary, Floros, Konstantinos V., primary, Jacob, Sheeba, primary, Chawla, Ayesha T., primary, Cai, Jinyang, primary, Hu, Bin, primary, Puchalapalli, Madhavi, primary, Coon, Colin M., primary, Khatri, Rishabh, primary, Crowther, Giovanna Stein, primary, Egan, Regina K., primary, Murchie, Ellen, primary, Greninger, Patricia, primary, Dalton, Krista M., primary, Ghotra, Maninderjit S., primary, Boikos, Sosipatros A., primary, Koblinski, Jennifer E., primary, Harada, Hisashi, primary, Sun, Yue, primary, Morgan, Iain M., primary, Basu, Devraj, primary, Dozmorov, Mikhail G., primary, Benes, Cyril H., primary, and Faber, Anthony C., primary

Published
2023
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9. Supplementary Table S1 from Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma

Author

Saha, Supriya K., primary, Gordan, John D., primary, Kleinstiver, Benjamin P., primary, Vu, Phuong, primary, Najem, Mortada S., primary, Yeo, Jia-Chi, primary, Shi, Lei, primary, Kato, Yasutaka, primary, Levin, Rebecca S., primary, Webber, James T., primary, Damon, Leah J., primary, Egan, Regina K., primary, Greninger, Patricia, primary, McDermott, Ultan, primary, Garnett, Mathew J., primary, Jenkins, Roger L., primary, Rieger-Christ, Kimberly M., primary, Sullivan, Travis B., primary, Hezel, Aram F., primary, Liss, Andrew S., primary, Mizukami, Yusuke, primary, Goyal, Lipika, primary, Ferrone, Cristina R., primary, Zhu, Andrew X., primary, Joung, J. Keith, primary, Shokat, Kevan M., primary, Benes, Cyril H., primary, and Bardeesy, Nabeel, primary

Published
2023
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10. Data from Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma

Author

Saha, Supriya K., primary, Gordan, John D., primary, Kleinstiver, Benjamin P., primary, Vu, Phuong, primary, Najem, Mortada S., primary, Yeo, Jia-Chi, primary, Shi, Lei, primary, Kato, Yasutaka, primary, Levin, Rebecca S., primary, Webber, James T., primary, Damon, Leah J., primary, Egan, Regina K., primary, Greninger, Patricia, primary, McDermott, Ultan, primary, Garnett, Mathew J., primary, Jenkins, Roger L., primary, Rieger-Christ, Kimberly M., primary, Sullivan, Travis B., primary, Hezel, Aram F., primary, Liss, Andrew S., primary, Mizukami, Yusuke, primary, Goyal, Lipika, primary, Ferrone, Cristina R., primary, Zhu, Andrew X., primary, Joung, J. Keith, primary, Shokat, Kevan M., primary, Benes, Cyril H., primary, and Bardeesy, Nabeel, primary

Published
2023
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11. Supplementary Figure Legends, Figures S1 - S6 from Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma

Author

Saha, Supriya K., primary, Gordan, John D., primary, Kleinstiver, Benjamin P., primary, Vu, Phuong, primary, Najem, Mortada S., primary, Yeo, Jia-Chi, primary, Shi, Lei, primary, Kato, Yasutaka, primary, Levin, Rebecca S., primary, Webber, James T., primary, Damon, Leah J., primary, Egan, Regina K., primary, Greninger, Patricia, primary, McDermott, Ultan, primary, Garnett, Mathew J., primary, Jenkins, Roger L., primary, Rieger-Christ, Kimberly M., primary, Sullivan, Travis B., primary, Hezel, Aram F., primary, Liss, Andrew S., primary, Mizukami, Yusuke, primary, Goyal, Lipika, primary, Ferrone, Cristina R., primary, Zhu, Andrew X., primary, Joung, J. Keith, primary, Shokat, Kevan M., primary, Benes, Cyril H., primary, and Bardeesy, Nabeel, primary

Published
2023
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12. Genome‐wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy

Author

Sahu, Avinash Das, S Lee, Joo, Wang, Zhiyong, Zhang, Gao, Iglesias‐Bartolome, Ramiro, Tian, Tian, Wei, Zhi, Miao, Benchun, Nair, Nishanth Ulhas, Ponomarova, Olga, Friedman, Adam A, Amzallag, Arnaud, Moll, Tabea, Kasumova, Gyulnara, Greninger, Patricia, Egan, Regina K, Damon, Leah J, Frederick, Dennie T, Jerby‐Arnon, Livnat, Wagner, Allon, Cheng, Kuoyuan, Park, Seung Gu, Robinson, Welles, Gardner, Kevin, Boland, Genevieve, Hannenhalli, Sridhar, Herlyn, Meenhard, Benes, Cyril, Flaherty, Keith, Luo, Ji, Gutkind, J Silvio, and Ruppin, Eytan

Published
2019
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13. Figure S2 from KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition

Author

Misale, Sandra, primary, Fatherree, Jackson P., primary, Cortez, Eliane, primary, Li, Chendi, primary, Bilton, Samantha, primary, Timonina, Daria, primary, Myers, David T., primary, Lee, Dana, primary, Gomez-Caraballo, Maria, primary, Greenberg, Max, primary, Nangia, Varuna, primary, Greninger, Patricia, primary, Egan, Regina K., primary, McClanaghan, Joseph, primary, Stein, Giovanna T., primary, Murchie, Ellen, primary, Zarrinkar, Patrick P., primary, Janes, Matthew R., primary, Li, Lian-Sheng, primary, Liu, Yi, primary, Hata, Aaron N., primary, and Benes, Cyril H., primary

Published
2023
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14. Data S1 from KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition

Author

Misale, Sandra, primary, Fatherree, Jackson P., primary, Cortez, Eliane, primary, Li, Chendi, primary, Bilton, Samantha, primary, Timonina, Daria, primary, Myers, David T., primary, Lee, Dana, primary, Gomez-Caraballo, Maria, primary, Greenberg, Max, primary, Nangia, Varuna, primary, Greninger, Patricia, primary, Egan, Regina K., primary, McClanaghan, Joseph, primary, Stein, Giovanna T., primary, Murchie, Ellen, primary, Zarrinkar, Patrick P., primary, Janes, Matthew R., primary, Li, Lian-Sheng, primary, Liu, Yi, primary, Hata, Aaron N., primary, and Benes, Cyril H., primary

Published
2023
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15. Pharmacologic Inhibition of SHP2 Blocks Both PI3K and MEK Signaling in Low-epiregulin HNSCC via GAB1

Author

Kurupi, Richard, primary, Floros, Konstantinos V., additional, Jacob, Sheeba, additional, Chawla, Ayesha T., additional, Cai, Jinyang, additional, Hu, Bin, additional, Puchalapalli, Madhavi, additional, Coon, Colin M., additional, Khatri, Rishabh, additional, Crowther, Giovanna Stein, additional, Egan, Regina K., additional, Murchie, Ellen, additional, Greninger, Patricia, additional, Dalton, Krista M., additional, Ghotra, Maninderjit S., additional, Boikos, Sosipatros A., additional, Koblinski, Jennifer E., additional, Harada, Hisashi, additional, Sun, Yue, additional, Morgan, Iain M., additional, Basu, Devraj, additional, Dozmorov, Mikhail G., additional, Benes, Cyril H., additional, and Faber, Anthony C., additional

Published
2022
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16. High-risk neuroblastoma with NF1 loss of function is targetable using SHP2 inhibition

Author

Cai, Jinyang, primary, Jacob, Sheeba, additional, Kurupi, Richard, additional, Dalton, Krista M., additional, Coon, Colin, additional, Greninger, Patricia, additional, Egan, Regina K., additional, Stein, Giovanna T., additional, Murchie, Ellen, additional, McClanaghan, Joseph, additional, Adachi, Yuta, additional, Hirade, Kentaro, additional, Dozmorov, Mikhail, additional, Glod, John, additional, Boikos, Sosipatros A., additional, Ebi, Hiromichi, additional, Hao, Huaixiang, additional, Caponigro, Giordano, additional, Benes, Cyril H., additional, and Faber, Anthony C., additional

Published
2022
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17. A landscape of synergistic drug combinations in non-small-cell lung cancer

Author

Nair, Nishanth Ulhas, primary, Greninger, Patricia, additional, Friedman, Adam, additional, Amzallag, Arnaud, additional, Cortez, Eliane, additional, Sahu, Avinash Das, additional, Lee, Joo Sang, additional, Dastur, Anahita, additional, Egan, Regina K., additional, Murchie, Ellen, additional, Crowther, Giovanna Stein, additional, McClanaghan, Joseph, additional, Boisvert, Jessica, additional, Damon, Leah, additional, Ho, Jeffrey, additional, Tam, Angela, additional, Garnett, Mathew J, additional, Engelman, Jeffrey A., additional, Haber, Daniel A., additional, Ruppin, Eytan, additional, and Benes, Cyril H., additional

Published
2021
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18. Catastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN -amplified neuroblastoma

Author

Dalton, Krista M., primary, Lochmann, Timothy L., additional, Floros, Konstantinos V., additional, Calbert, Marissa L., additional, Kurupi, Richard, additional, Stein, Giovanna T., additional, McClanaghan, Joseph, additional, Murchie, Ellen, additional, Egan, Regina K., additional, Greninger, Patricia, additional, Dozmorov, Mikhail, additional, Ramamoorthy, Sivapriya, additional, Puchalapalli, Madhavi, additional, Hu, Bin, additional, Shock, Lisa, additional, Koblinski, Jennifer, additional, Glod, John, additional, Boikos, Sosipatros A., additional, Benes, Cyril H., additional, and Faber, Anthony C., additional

Published
2021
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19. Abstract PO-024: Catastrophic ATP loss underlines a metabolic combination therapy tailored for MYCN-amplified neuroblastoma

Author

Powell, Krista M., primary, Lochmann, Timonthy L., additional, Floros, Konstantinos V., additional, Calbert, Marissa L., additional, Kurupi, Richard, additional, Stein, Giovanna T., additional, McClanaghan, Joseph, additional, Murchie, Ellen, additional, Egan, Regina K., additional, Greninger, Patricia, additional, Dozmorov, Mikhail, additional, Ramamoorthy, Sivapriya, additional, Puchalapalli, Madhavi, additional, Hu, Bin, additional, Shock, Lisa, additional, Koblisnski, Jennifer, additional, Glod, John, additional, Boikos, Sosipatros A., additional, Benes, Cyril H., additional, and Faber, Anthony C., additional

Published
2020
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20. KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition

Author

Misale, Sandra, primary, Fatherree, Jackson P., additional, Cortez, Eliane, additional, Li, Chendi, additional, Bilton, Samantha, additional, Timonina, Daria, additional, Myers, David T., additional, Lee, Dana, additional, Gomez-Caraballo, Maria, additional, Greenberg, Max, additional, Nangia, Varuna, additional, Greninger, Patricia, additional, Egan, Regina K., additional, McClanaghan, Joseph, additional, Stein, Giovanna T., additional, Murchie, Ellen, additional, Zarrinkar, Patrick P., additional, Janes, Matthew R., additional, Li, Lian-Sheng, additional, Liu, Yi, additional, Hata, Aaron N., additional, and Benes, Cyril H., additional

Published
2019
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21. AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies

Author

Caenepeel, Sean, primary, Brown, Sean P., additional, Belmontes, Brian, additional, Moody, Gordon, additional, Keegan, Kathleen S., additional, Chui, Danny, additional, Whittington, Douglas A., additional, Huang, Xin, additional, Poppe, Leszek, additional, Cheng, Alan C., additional, Cardozo, Mario, additional, Houze, Jonathan, additional, Li, Yunxiao, additional, Lucas, Brian, additional, Paras, Nick A., additional, Wang, Xianghong, additional, Taygerly, Joshua P., additional, Vimolratana, Marc, additional, Zancanella, Manuel, additional, Zhu, Liusheng, additional, Cajulis, Elaina, additional, Osgood, Tao, additional, Sun, Jan, additional, Damon, Leah, additional, Egan, Regina K., additional, Greninger, Patricia, additional, McClanaghan, Joseph D., additional, Gong, Jianan, additional, Moujalled, Donia, additional, Pomilio, Giovanna, additional, Beltran, Pedro, additional, Benes, Cyril H., additional, Roberts, Andrew W., additional, Huang, David C., additional, Wei, Andrew, additional, Canon, Jude, additional, Coxon, Angela, additional, and Hughes, Paul E., additional

Published
2018
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22. BRAF and AXL oncogenes drive RIPK3 expression loss in cancer

Author

Najafov, Ayaz, primary, Zervantonakis, Ioannis K., additional, Mookhtiar, Adnan K., additional, Greninger, Patricia, additional, March, Ryan J., additional, Egan, Regina K., additional, Luu, Hoang Son, additional, Stover, Daniel G., additional, Matulonis, Ursula A., additional, Benes, Cyril H., additional, and Yuan, Junying, additional

Published
2018
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24. Genome-wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy

Author

Das, Avinash, primary, Lee, Joo Sang, additional, Zhang, Gao, additional, Wang, Zhiyong, additional, Iglesias-Bartolome, Ramiro, additional, Tian, Tian, additional, Wei, Zhi, additional, Miao, Benchun, additional, Nair, Nishanth Ulhas, additional, Ponomarova, Olga, additional, Friedman, Adam A., additional, Amzallag, Arnaud, additional, Moll, Tabea, additional, Kasumova, Gyulnara, additional, Greninger, Patricia, additional, Egan, Regina K., additional, Damon, Leah J., additional, Frederick, Dennie T., additional, Wagner, Allon, additional, Cheng, Kuoyuan, additional, Park, Seung Gu, additional, Robinson, Welles, additional, Gardner, Kevin, additional, Boland, Genevieve, additional, Hannenhalli, Sridhar, additional, Herlyn, Meenhard, additional, Benes, Cyril, additional, Gutkind, J. Silvio, additional, Flaherty, Keith, additional, and Ruppin, Eytan, additional

Published
2018
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25. A Landscape of Pharmacogenomic Interactions in Cancer

Author

Iorio, Francesco, primary, Knijnenburg, Theo A., additional, Vis, Daniel J., additional, Bignell, Graham R., additional, Menden, Michael P., additional, Schubert, Michael, additional, Aben, Nanne, additional, Gonçalves, Emanuel, additional, Barthorpe, Syd, additional, Lightfoot, Howard, additional, Cokelaer, Thomas, additional, Greninger, Patricia, additional, van Dyk, Ewald, additional, Chang, Han, additional, de Silva, Heshani, additional, Heyn, Holger, additional, Deng, Xianming, additional, Egan, Regina K., additional, Liu, Qingsong, additional, Mironenko, Tatiana, additional, Mitropoulos, Xeni, additional, Richardson, Laura, additional, Wang, Jinhua, additional, Zhang, Tinghu, additional, Moran, Sebastian, additional, Sayols, Sergi, additional, Soleimani, Maryam, additional, Tamborero, David, additional, Lopez-Bigas, Nuria, additional, Ross-Macdonald, Petra, additional, Esteller, Manel, additional, Gray, Nathanael S., additional, Haber, Daniel A., additional, Stratton, Michael R., additional, Benes, Cyril H., additional, Wessels, Lodewyk F.A., additional, Saez-Rodriguez, Julio, additional, McDermott, Ultan, additional, and Garnett, Mathew J., additional

Published
2016
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26. Genome‐wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy.

Author

Park, Seung Gu, Sahu, Avinash Das, Ponomarova, Olga, Jerby‐Arnon, Livnat, Wagner, Allon, Miao, Benchun, Friedman, Adam A, Amzallag, Arnaud, Moll, Tabea, Kasumova, Gyulnara, Greninger, Patricia, Egan, Regina K, Damon, Leah J, Frederick, Dennie T, Boland, Genevieve, Benes, Cyril, Flaherty, Keith, Cheng, Kuoyuan, Robinson, Welles, and Hannenhalli, Sridhar

Subjects
PHARMACOGENOMICS, CANCER, DRUG resistance, IMMUNOTHERAPY, DATA analysis
Abstract

Most patients with advanced cancer eventually acquire resistance to targeted therapies, spurring extensive efforts to identify molecular events mediating therapy resistance. Many of these events involve synthetic rescue (SR) interactions, where the reduction in cancer cell viability caused by targeted gene inactivation is rescued by an adaptive alteration of another gene (the rescuer). Here, we perform a genome‐wide in silico prediction of SR rescuer genes by analyzing tumor transcriptomics and survival data of 10,000 TCGA cancer patients. Predicted SR interactions are validated in new experimental screens. We show that SR interactions can successfully predict cancer patients' response and emerging resistance. Inhibiting predicted rescuer genes sensitizes resistant cancer cells to therapies synergistically, providing initial leads for developing combinatorial approaches to overcome resistance proactively. Finally, we show that the SR analysis of melanoma patients successfully identifies known mediators of resistance to immunotherapy and predicts novel rescuers. Synopsis: In silico prediction of synthetic rescue genetic interactions identifies gene involved in resistance to targeted immunotherapy, which determines patients' clinical response. Inhibiting predicted genes sensitizes cancer cells to cancer therapies, laying a basis for developing new drug combinations. An in silico method is presented that identifies synthetic rescue genetic interactions whereby the loss of fitness due to the deletion of one gene is compensated by the altered activity of another rescuer gene.Genes are identified that mediate therapy resistance in cancer and that predict clinical response to targeted therapy in patients.Synthetic rescue interactions predict resistance mechanism to immunotherapy and inhibition of rescuer genes sensitizes resistant cancer cells to therapies. In silico prediction of synthetic rescue genetic interactions identifies gene involved in resistance to targeted immunotherapy, which determines patients' clinical response. Inhibiting predicted genes sensitizes cancer cells to cancer therapies, laying a basis for developing new drug combinations. [ABSTRACT FROM AUTHOR]

Published
2019
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