Integrated CRISPR screening and drug profiling identifies combination opportunities for EGFR, ALK, and BRAF/MEK inhibitors

被引：9

作者：

Tiedt, Ralph ^{[1
,4
]}

King, Frederick J. ^{[2
]}

Stamm, Christelle ^{[1
]}

Niederst, Matthew J. ^{[3
]}

Delach, Scott ^{[3
]}

Zumstein-Mecker, Sabine ^{[1
]}

Meltzer, Jodi ^{[3
]}

Mulford, Iain J. ^{[3
]}

Labrot, Emma ^{[3
,9
]}

Engstler, Barbara Schacher ^{[1
]}

Baltschukat, Sabrina ^{[1
]}

Kerr, Grainne ^{[1
]}

Golji, Javad ^{[3
,10
]}

Wyss, Daniel ^{[1
]}

Schnell, Christian ^{[1
]}

Ainscow, Edward ^{[2
,7
]}

Engelman, Jeffrey A. ^{[3
,12
]}

Sellers, William R. ^{[3
,5
,6
]}

Barretina, Jordi ^{[3
,8
]}

Caponigro, Giordano ^{[3
]}

Porta, Diana Graus ^{[1
,11
]}

机构：

[1] Novartis Inst Biomed Res, Oncol Dis Area, Basel, Switzerland

[2] Genom Inst Novartis Res Fdn, Novartis Inst Biomed Res, La Jolla, CA USA

[3] Novartis Inst Biomed Res, Oncol Dis Area, Cambridge, MA 02139 USA

[4] Monte Rosa Therapeut, Basel, Switzerland

[5] Broad Inst MIT & Harvard, Cambridge, MA USA

[6] Dana Farber Canc Inst, Boston, MA USA

[7] Carrick Therapeut, Dublin, Ireland

[8] Inst Hlth Sci Res Germans Trias i Pujol IGTP, Barcelona, Spain

[9] Sanofi, Waltham, MA USA

[10] MOMA Therapeut, Boston, MA USA

[11] Ridgeline Therapeut, Basel, Switzerland

[12] Treeline Biosci, Watertown, MA USA

来源：

CELL REPORTS | 2023年 / 42卷 / 04期

关键词：

LUNG-CANCER; ACQUIRED-RESISTANCE; NAZARTINIB EGF816; PHASE-I; OSIMERTINIB; ACTIVATION; LUCIFERASE; SAFETY; CELLS; MCL1;

D O I：

10.1016/j.celrep.2023.112297

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Anti-tumor efficacy of targeted therapies is variable across patients and cancer types. Even in patients with initial deep response, tumors are typically not eradicated and eventually relapse. To address these chal-lenges, we present a systematic screen for targets that limit the anti-tumor efficacy of EGFR and ALK inhib-itors in non-small cell lung cancer and BRAF/MEK inhibitors in colorectal cancer. Our approach includes genome-wide CRISPR screens with or without drugs targeting the oncogenic driver ("anchor therapy"), and large-scale pairwise combination screens of anchor therapies with 351 other drugs. Interestingly, target-ing of a small number of genes, including MCL1, BCL2L1, and YAP1, sensitizes multiple cell lines to the respective anchor therapy. Data from drug combination screens with EGF816 and ceritinib indicate that da-satinib and agents disrupting microtubules act synergistically across many cell lines. Finally, we show that a higher-order-combination screen with 26 selected drugs in two resistant EGFR-mutant lung cancer cell lines identified active triplet combinations.

引用

页数：19

共 62 条

[1] Capmatinib (INC280) Is Active Against Models of Non-Small Cell Lung Cancer and Other Cancer Types with Defined Mechanisms of MET Activation [J].

Baltschukat, Sabrina ;

Engstler, Barbara Schacher ;

Huang, Alan ;

Hao, Huai-Xiang ;

Tam, Angela ;

Wang, Hui Qin ;

Liang, Jinsheng ;

DiMare, Matthew T. ;

Bhang, Hyo-Eun Carrie ;

Wang, Youzhen ;

Furet, Pascal ;

Sellers, William R. ;

Hofmann, Francesco ;

Schoepfer, Joseph ;

Tiedt, Ralph .

CLINICAL CANCER RESEARCH, 2019, 25 (10) :3164-3175

[2] The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity (vol 483, pg 603, 2012) [J].

Barretina, Jordi ;

Caponigro, Giordano ;

Stransky, Nicolas ;

Venkatesan, Kavitha ;

Margolin, Adam A. ;

Kim, Sungjoon ;

Wilson, Christopher J. ;

Lehar, Joseph ;

Kryukov, Gregory V. ;

Sonkin, Dmitriy ;

Reddy, Anupama ;

Liu, Manway ;

Murray, Lauren ;

Berger, Michael F. ;

Monahan, John E. ;

Morais, Paula ;

Meltzer, Jodi ;

Korejwa, Adam ;

Jane-Valbuena, Judit ;

Mapa, Felipa A. ;

Thibault, Joseph ;

Bric-Furlong, Eva ;

Raman, Pichai ;

Shipway, Aaron ;

Engels, Ingo H. ;

Cheng, Jill ;

Yu, Guoying K. ;

Yu, Jianjun ;

Aspesi, Peter, Jr. ;

de Silva, Melanie ;

Jagtap, Kalpana ;

Jones, Michael D. ;

Wang, Li ;

Hatton, Charles ;

Palescandolo, Emanuele ;

Gupta, Supriya ;

Mahan, Scott ;

Sougnez, Carrie ;

Onofrio, Robert C. ;

Liefeld, Ted ;

MacConaill, Laura ;

Winckler, Wendy ;

Reich, Michael ;

Li, Nanxin ;

Mesirov, Jill P. ;

Gabriel, Stacey B. ;

Getz, Gad ;

Ardlie, Kristin ;

Chan, Vivien ;

Myer, Vic E. .

NATURE, 2019, 565 (7738) :E5-E6

[3] The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity [J].

Barretina, Jordi ;

Caponigro, Giordano ;

Stransky, Nicolas ;

Venkatesan, Kavitha ;

Margolin, Adam A. ;

Kim, Sungjoon ;

Wilson, Christopher J. ;

Lehar, Joseph ;

Kryukov, Gregory V. ;

Sonkin, Dmitriy ;

Reddy, Anupama ;

Liu, Manway ;

Murray, Lauren ;

Berger, Michael F. ;

Monahan, John E. ;

Morais, Paula ;

Meltzer, Jodi ;

Korejwa, Adam ;

Jane-Valbuena, Judit ;

Mapa, Felipa A. ;

Thibault, Joseph ;

Bric-Furlong, Eva ;

Raman, Pichai ;

Shipway, Aaron ;

Engels, Ingo H. ;

Cheng, Jill ;

Yu, Guoying K. ;

Yu, Jianjun ;

Aspesi, Peter, Jr. ;

de Silva, Melanie ;

Jagtap, Kalpana ;

Jones, Michael D. ;

Wang, Li ;

Hatton, Charles ;

Palescandolo, Emanuele ;

Gupta, Supriya ;

Mahan, Scott ;

Sougnez, Carrie ;

Onofrio, Robert C. ;

Liefeld, Ted ;

MacConaill, Laura ;

Winckler, Wendy ;

Reich, Michael ;

Li, Nanxin ;

Mesirov, Jill P. ;

Gabriel, Stacey B. ;

Getz, Gad ;

Ardlie, Kristin ;

Chan, Vivien ;

Myer, Vic E. .

NATURE, 2012, 483 (7391) :603-607

[4] Humanized Mcl-1 mice enable accurate preclinical evaluation of MCL-1 inhibitors destined for clinical use [J].

Brennan, Margs S. ;

Chang, Catherine ;

Tai, Lin ;

Lessene, Guillaume ;

Strasser, Andreas ;

Dewson, Grant ;

Kelly, Gemma L. ;

Herold, Marco J. .

BLOOD, 2018, 132 (15) :1573-1583

[5] Systematic Chemogenetic Library Assembly [J].

Canham, Stephen M. ;

Wang, Yuan ;

Cornett, Allen ;

Auld, Douglas S. ;

Baeschlin, Daniel K. ;

Patoor, Maude ;

Skaanderup, Philip R. ;

Honda, Ayako ;

Llamas, Luis ;

Wendel, Greg ;

Mapa, Felipa A. ;

Aspesi, Peter, Jr. ;

Labbe-Giguere, Nancy ;

Gamber, Gabriel G. ;

Palacios, Daniel S. ;

Schuffenhauer, Ansgar ;

Deng, Zhan ;

Nigsch, Florian ;

Frederiksen, Mathias ;

Bushell, Simon M. ;

Rothman, Deborah ;

Jain, Rishi K. ;

Hemmerle, Horst ;

Briner, Karin ;

Porter, Jeffery A. ;

Tallarico, John A. ;

Jenkins, Jeremy L. .

CELL CHEMICAL BIOLOGY, 2020, 27 (09) :1124-1129

[6] Targeting pan-essential genes in cancer: Challenges and opportunities [J].

Chang, Liang ;

Ruiz, Paloma ;

Ito, Takahiro ;

Sellers, William R. .

CANCER CELL, 2021, 39 (04) :466-479

[7] A Novel Combination Treatment Targeting BCL-XL and MCL1 for KRAS/BRAF-mutated and BCL2L1-amplified Colorectal Cancers [J].

Cho, Sung-Yup ;

Han, Jee Yun ;

Na, Deukchae ;

Kang, Wonyoung ;

Lee, Ahra ;

Kim, Jooyoung ;

Lee, Jieun ;

Min, Seoyeon ;

Kang, Jinjoo ;

Chae, Jeesoo ;

Kim, Jong-Il ;

Park, Hansoo ;

Lee, Won-Suk ;

Lee, Charles .

MOLECULAR CANCER THERAPEUTICS, 2017, 16 (10) :2178-2190

[8] Combined BRAF, EGFR, and MEK Inhibition in Patients with &ITBRAF&ITV600E-Mutant Colorectal Cancer [J].

Corcoran, Ryan B. ;

Andre, Thierry ;

Atreya, Chloe E. ;

Schellens, Jan H. M. ;

Yoshino, Takayuki ;

Bendell, Johanna C. ;

Hollebecque, Antoine ;

McRee, Autumn J. ;

Siena, Salvatore ;

Middleton, Gary ;

Muro, Kei ;

Gordon, Michael S. ;

Tabernero, Josep ;

Yaeger, Rona ;

O'Dwyer, Peter J. ;

Humblet, Yves ;

De Vos, Filip ;

Jung, A. Scott ;

Brase, Jan C. ;

Jaeger, Savina ;

Bettinger, Severine ;

Mookerjee, Bijoyesh ;

Rangwala, Fatima ;

Van Cutsem, Eric .

CANCER DISCOVERY, 2018, 8 (04) :428-443

[9] Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer [J].

Corcoran, Ryan B. ;

Atreya, Chloe E. ;

Falchook, Gerald S. ;

Kwak, Eunice L. ;

Ryan, David P. ;

Bendell, Johanna C. ;

Hamid, Omid ;

Messersmith, Wells A. ;

Daud, Adil ;

Kurzrock, Razelle ;

Pierobon, Mariaelena ;

Sun, Peng ;

Cunningham, Elizabeth ;

Little, Shonda ;

Orford, Keith ;

Motwani, Monica ;

Bai, Yuchen ;

Patel, Kiran ;

Venook, Alan P. ;

Kopetz, Scott .

JOURNAL OF CLINICAL ONCOLOGY, 2015, 33 (34) :4023-+

[10] Patient-derived models of acquired resistance can identify effective drug combinations for cancer [J].

Crystal, Adam S. ;

Shaw, Alice T. ;

Sequist, Lecia V. ;

Friboulet, Luc ;

Niederst, Matthew J. ;

Lockerman, Elizabeth L. ;

Frias, Rosa L. ;

Gainor, Justin F. ;

Amzallag, Arnaud ;

Greninger, Patricia ;

Lee, Dana ;

Kalsy, Anuj ;

Gomez-Caraballo, Maria ;

Elamine, Leila ;

Howe, Emily ;

Hur, Wooyoung ;

Lifshits, Eugene ;

Robinson, Hayley E. ;

Katayama, Ryohei ;

Faber, Anthony C. ;

Awad, Mark M. ;

Ramaswamy, Sridhar ;

Mino-Kenudson, Mari ;

Iafrate, A. John ;

Benes, Cyril H. ;

Engelman, Jeffrey A. .

SCIENCE, 2014, 346 (6216) :1480-1486

← 1 2 3 4 5 6 7 →