Concurrent Mutations in STK11 and KEAP1 Promote Ferroptosis Protection and SCD1 Dependence in Lung Cancer

被引：179

作者：

Wohlhieter, Corrin A. ^{[1
]}

Richards, Allison L. ^{[2
]}

Uddin, Fathema ^{[3
]}

Hulton, Christopher H. ^{[4
]}

Quintanal-Villalonga, Alvaro ^{[3
]}

Martin, Axel ^{[5
]}

de Stanchina, Elisa ^{[6
]}

Bhanot, Umeshkumar ^{[7
]}

Asher, Marina ^{[7
]}

Shah, Nisargbhai S. ^{[3
]}

Hayatt, Omar ^{[6
]}

Buonocore, Darren J. ^{[8
]}

Rekhtman, Natasha ^{[8
]}

Shen, Ronglai ^{[5
]}

Arbour, Kathryn C. ^{[3
]}

Donoghue, Mark ^{[2
]}

Poirier, John T. ^{[9
]}

Sen, Triparna ^{[3
,10
]}

Rudin, Charles M. ^{[1
,3
,4
,10
]}

机构：

[1] Weill Cornell Med, Grad Program Pharmacol, New York, NY 10021 USA

[2] Mem Sloan Kettering Canc Ctr, Marie Josee & Henry R Kravis Ctr Mol Oncol, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[4] Mem Sloan Kettering Canc Ctr, Louis V Gerstner Jr Grad Sch Biomed Sci, New York, NY 10065 USA

[5] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA

[6] Mem Sloan Kettering Canc Ctr, Antitumor Assessment Core, New York, NY 10065 USA

[7] Mem Sloan Kettering Canc Ctr, Precis Pathol Biobanking Ctr, New York, NY 10065 USA

[8] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[9] New York Univ Langone Hlth, Perlmutter Canc Ctr, New York, NY 10016 USA

[10] Mem Sloan Kettering Canc Ctr, Mol Pharmacol Program, New York, NY 10065 USA

来源：

CELL REPORTS | 2020年 / 33卷 / 09期

关键词：

STEAROYL-COA DESATURASE-1; ALDO-KETO REDUCTASES; AKR1C1; IDENTIFICATION; PROLIFERATION; EXPRESSION; TARGET; GENES;

D O I：

10.1016/j.celrep.2020.108444

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Concurrent loss-of-function mutations in STK11 and KEAP1 in lung adenocarcinoma (LUAD) are associated with aggressive tumor growth, resistance to available therapies, and early death. We investigated the effects of coordinate STK11 and KEAP1 loss by comparing co-mutant with single mutant and wild-type isogenic counterparts in multiple LUAD models. STK11/KEAP1 co-mutation results in significantly elevated expression of ferroptosis-protective genes, including SCD and AKR1C1/2/3, and resistance to pharmacologically induced ferroptosis. CRISPR screening further nominates SCD (SCD1) as selectively essential in STK11/KEAP1 co-mutant LUAD. Genetic and pharmacological inhibition of SCD1 confirms the essentiality of this gene and augments the effects of ferroptosis induction by erastin and RSL3. Together these data identify SCD1 as a selective vulnerability and a promising candidate for targeted drug development in STK11/KEAP1 co-mutant LUAD.

引用

页数：23

共 42 条

[1] Effects of Co-occurring Genomic Alterations on Outcomes in Patients with KRAS-Mutant Non-Small Cell Lung Cancer [J].

Arbour, Kathryn C. ;

Jordan, Emmett ;

Kim, Hyunjae Ryan ;

Dienstag, Jordan ;

Yu, Helena A. ;

Sanchez-Vega, Francisco ;

Lito, Piro ;

Berger, Michael ;

Solit, David B. ;

Hellmann, Matthew ;

Kris, Mark G. ;

Rudin, Charles M. ;

Ni, Ai ;

Arcila, Maria ;

Ladanyi, Marc ;

Riely, Gregory J. .

CLINICAL CANCER RESEARCH, 2018, 24 (02) :334-340

[2]

Bray F, 2018, CA-CANCER J CLIN, V68, P394, DOI [10.3322/caac.21492, 10.3322/caac.21609]

[3] Near-optimal probabilistic RNA-seq quantification [J].

Bray, Nicolas L. ;

Pimentel, Harold ;

Melsted, Pall ;

Pachter, Lior .

NATURE BIOTECHNOLOGY, 2016, 34 (05) :525-527

[4] The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data [J].

Cerami, Ethan ;

Gao, Jianjiong ;

Dogrusoz, Ugur ;

Gross, Benjamin E. ;

Sumer, Selcuk Onur ;

Aksoy, Buelent Arman ;

Jacobsen, Anders ;

Byrne, Caitlin J. ;

Heuer, Michael L. ;

Larsson, Erik ;

Antipin, Yevgeniy ;

Reva, Boris ;

Goldberg, Arthur P. ;

Sander, Chris ;

Schultz, Nikolaus .

CANCER DISCOVERY, 2012, 2 (05) :401-404

[5] AKR1C1 controls cisplatin-resistance in head and neck squamous cell carcinoma through cross-talk with the STAT1/3 signaling pathway [J].

Chang, Wei-Min ;

Chang, Yu-Chan ;

Yang, Yi-Chieh ;

Lin, Sze-Kwan ;

Chang, Peter Mu-Hsin ;

Hsiao, Michael .

JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, 2019, 38 (1)

[6] Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology [J].

Cheng, Donavan T. ;

Mitchell, Talia N. ;

Zehir, Ahmet ;

Shah, Ronak H. ;

Benayed, Ryma ;

Syed, Aijazuddin ;

Chandramohan, Raghu ;

Liu, Zhen Yu ;

Won, Helen H. ;

Scott, Sasinya N. ;

Brannon, A. Rose ;

O'Reilly, Catherine ;

Sadowska, Justyna ;

Casanova, Jacklyn ;

Yannes, Angela ;

Hechtman, Jaclyn F. ;

Yao, Jinjuan ;

Song, Wei ;

Ross, Dara S. ;

Oultache, Alifya ;

Dogan, Snjezana ;

Borsu, Laetitia ;

Hameed, Meera ;

Nafa, Khedoudja ;

Arcila, Maria E. ;

Ladanyi, Marc ;

Berger, Michael F. .

JOURNAL OF MOLECULAR DIAGNOSTICS, 2015, 17 (03) :251-264

[7]

Collisson E.A., 2014, NATURE, V511, P543

[8] NRF2 and the Hallmarks of Cancer [J].

de la Vega, Montserrat Rojo ;

Chapman, Eli ;

Zhang, Donna D. .

CANCER CELL, 2018, 34 (01) :21-43

[9] Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death [J].

Dixon, Scott J. ;

Lemberg, Kathryn M. ;

Lamprecht, Michael R. ;

Skouta, Rachid ;

Zaitsev, Eleina M. ;

Gleason, Caroline E. ;

Patel, Darpan N. ;

Bauer, Andras J. ;

Cantley, Alexandra M. ;

Yang, Wan Seok ;

Morrison, Barclay, III ;

Stockwell, Brent R. .

CELL, 2012, 149 (05) :1060-1072

[10] NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis [J].

Dodson, Matthew ;

Castro-Portuguez, Raul ;

Zhang, Donna D. .

REDOX BIOLOGY, 2019, 23

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