Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. Approximately 20–30% of human lung adenocarcinomas (LUADs) harbor mutations in Kelch-like ECH-associated protein 1 (KEAP1) that hyperactivate the nuclear factor, erythroid 2-like 2 (NFE2L2) antioxidant program. We previo...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2021
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| Online Access: | https://hdl.handle.net/1721.1/133110 |
| _version_ | 1826191295192760320 |
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| author | Romero, Rodrigo Sánchez-Rivera, Francisco J Westcott, Peter MK Mercer, Kim L Bhutkar, Arjun Muir, Alexander González Robles, Tania J Lamboy Rodríguez, Swanny Liao, Laura Z Ng, Sheng Rong Li, Leanne Colón, Caterina I Naranjo, Santiago Beytagh, Mary Clare Lewis, Caroline A Hsu, Peggy P Bronson, Roderick T Vander Heiden, Matthew G Jacks, Tyler |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Romero, Rodrigo Sánchez-Rivera, Francisco J Westcott, Peter MK Mercer, Kim L Bhutkar, Arjun Muir, Alexander González Robles, Tania J Lamboy Rodríguez, Swanny Liao, Laura Z Ng, Sheng Rong Li, Leanne Colón, Caterina I Naranjo, Santiago Beytagh, Mary Clare Lewis, Caroline A Hsu, Peggy P Bronson, Roderick T Vander Heiden, Matthew G Jacks, Tyler |
| author_sort | Romero, Rodrigo |
| collection | MIT |
| description | © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. Approximately 20–30% of human lung adenocarcinomas (LUADs) harbor mutations in Kelch-like ECH-associated protein 1 (KEAP1) that hyperactivate the nuclear factor, erythroid 2-like 2 (NFE2L2) antioxidant program. We previously showed that Kras-driven Keap1-mutant LUAD is highly aggressive and dependent on glutaminolysis. Here we performed a druggable genome CRISPR screen and uncovered a Keap1-mutant-specific dependency on solute carrier family 33 member 1 (Slc33a1), as well as several functionally related genes associated with the unfolded protein response. Genetic and biochemical experiments using mouse and human Keap1-mutant tumor lines, as well as preclinical genetically engineered mouse models, validate Slc33a1 as a robust Keap1-mutant-specific dependency. Furthermore, unbiased genome-wide CRISPR screening identified additional genes related to Slc33a1 dependency. Overall, our study provides a rationale for stratification of patients harboring KEAP1-mutant or NRF2-hyperactivated tumors as likely responders to targeted SLC33A1 inhibition and underscores the value of integrating functional genetic approaches with genetically engineered mouse models to identify and validate genotype-specific therapeutic targets. |
| first_indexed | 2024-09-23T08:54:00Z |
| format | Article |
| id | mit-1721.1/133110 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:54:00Z |
| publishDate | 2021 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1331102023-12-07T18:17:10Z Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1 Romero, Rodrigo Sánchez-Rivera, Francisco J Westcott, Peter MK Mercer, Kim L Bhutkar, Arjun Muir, Alexander González Robles, Tania J Lamboy Rodríguez, Swanny Liao, Laura Z Ng, Sheng Rong Li, Leanne Colón, Caterina I Naranjo, Santiago Beytagh, Mary Clare Lewis, Caroline A Hsu, Peggy P Bronson, Roderick T Vander Heiden, Matthew G Jacks, Tyler Koch Institute for Integrative Cancer Research at MIT Massachusetts Institute of Technology. Department of Biology © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. Approximately 20–30% of human lung adenocarcinomas (LUADs) harbor mutations in Kelch-like ECH-associated protein 1 (KEAP1) that hyperactivate the nuclear factor, erythroid 2-like 2 (NFE2L2) antioxidant program. We previously showed that Kras-driven Keap1-mutant LUAD is highly aggressive and dependent on glutaminolysis. Here we performed a druggable genome CRISPR screen and uncovered a Keap1-mutant-specific dependency on solute carrier family 33 member 1 (Slc33a1), as well as several functionally related genes associated with the unfolded protein response. Genetic and biochemical experiments using mouse and human Keap1-mutant tumor lines, as well as preclinical genetically engineered mouse models, validate Slc33a1 as a robust Keap1-mutant-specific dependency. Furthermore, unbiased genome-wide CRISPR screening identified additional genes related to Slc33a1 dependency. Overall, our study provides a rationale for stratification of patients harboring KEAP1-mutant or NRF2-hyperactivated tumors as likely responders to targeted SLC33A1 inhibition and underscores the value of integrating functional genetic approaches with genetically engineered mouse models to identify and validate genotype-specific therapeutic targets. 2021-10-25T18:57:39Z 2021-10-25T18:57:39Z 2020 2021-08-27T13:05:04Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/133110 Romero, Rodrigo, Sánchez-Rivera, Francisco J, Westcott, Peter MK, Mercer, Kim L, Bhutkar, Arjun et al. 2020. "Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1." Nature Cancer, 1 (6). en 10.1038/S43018-020-0071-1 Nature Cancer Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Springer Science and Business Media LLC PMC |
| spellingShingle | Romero, Rodrigo Sánchez-Rivera, Francisco J Westcott, Peter MK Mercer, Kim L Bhutkar, Arjun Muir, Alexander González Robles, Tania J Lamboy Rodríguez, Swanny Liao, Laura Z Ng, Sheng Rong Li, Leanne Colón, Caterina I Naranjo, Santiago Beytagh, Mary Clare Lewis, Caroline A Hsu, Peggy P Bronson, Roderick T Vander Heiden, Matthew G Jacks, Tyler Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1 |
| title | Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1 |
| title_full | Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1 |
| title_fullStr | Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1 |
| title_full_unstemmed | Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1 |
| title_short | Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1 |
| title_sort | keap1 mutation renders lung adenocarcinomas dependent on slc33a1 |
| url | https://hdl.handle.net/1721.1/133110 |
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