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

Corrin A. Wohlhieter; Allison L. Richards; Fathema Uddin; Christopher H. Hulton; Àlvaro Quintanal-Villalonga; Axel Martin; Elisa de Stanchina; Umeshkumar Bhanot; Marina Asher; Nisargbhai S. Shah; Omar Hayatt; Darren J. Buonocore; Natasha Rekhtman; Ronglai Shen; Kathryn C. Arbour; Mark Donoghue; John T. Poirier; Triparna Sen; Charles M. Rudin

doi:10.1016/j.celrep.2020.108444

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

Corrin A. Wohlhieter, Allison L. Richards, Fathema Uddin, Christopher H. Hulton, Àlvaro Quintanal-Villalonga, Axel Martin, Elisa de Stanchina, Umeshkumar Bhanot, Marina Asher, Nisargbhai S. Shah, Omar Hayatt, Darren J. Buonocore, Natasha Rekhtman, Ronglai Shen, Kathryn C. Arbour, Mark Donoghue, John T. Poirier, Triparna Sen, Charles M. Rudin

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135 Scopus citations

Abstract

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.

Original language	English
Article number	108444
Journal	Cell Reports
Volume	33
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2020.108444
State	Published - 1 Dec 2020
Externally published	Yes

Keywords

AKR1C1
CRISPR
KEAP1
LKB1
NSCLC
SCD1
STK11
ferroptosis

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Wohlhieter, C. A., Richards, A. L., Uddin, F., Hulton, C. H., Quintanal-Villalonga, À., Martin, A., de Stanchina, E., Bhanot, U., Asher, M., Shah, N. S., Hayatt, O., Buonocore, D. J., Rekhtman, N., Shen, R., Arbour, K. C., Donoghue, M., Poirier, J. T., Sen, T., & Rudin, C. M. (2020). Concurrent Mutations in STK11 and KEAP1 Promote Ferroptosis Protection and SCD1 Dependence in Lung Cancer. Cell Reports, 33(9), Article 108444. https://doi.org/10.1016/j.celrep.2020.108444

@article{80e0aa932a9a4bdc8ffcaf25ed6f1083,

title = "Concurrent Mutations in STK11 and KEAP1 Promote Ferroptosis Protection and SCD1 Dependence in Lung Cancer",

abstract = "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.",

keywords = "AKR1C1, CRISPR, KEAP1, LKB1, NSCLC, SCD1, STK11, ferroptosis",

author = "Wohlhieter, {Corrin A.} and Richards, {Allison L.} and Fathema Uddin and Hulton, {Christopher H.} and {\`A}lvaro Quintanal-Villalonga and Axel Martin and {de Stanchina}, Elisa and Umeshkumar Bhanot and Marina Asher and Shah, {Nisargbhai S.} and Omar Hayatt and Buonocore, {Darren J.} and Natasha Rekhtman and Ronglai Shen and Arbour, {Kathryn C.} and Mark Donoghue and Poirier, {John T.} and Triparna Sen and Rudin, {Charles M.}",

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s)",

year = "2020",

month = dec,

day = "1",

doi = "10.1016/j.celrep.2020.108444",

language = "English",

volume = "33",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

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Wohlhieter, CA, Richards, AL, Uddin, F, Hulton, CH, Quintanal-Villalonga, À, Martin, A, de Stanchina, E, Bhanot, U, Asher, M, Shah, NS, Hayatt, O, Buonocore, DJ, Rekhtman, N, Shen, R, Arbour, KC, Donoghue, M, Poirier, JT, Sen, T & Rudin, CM 2020, 'Concurrent Mutations in STK11 and KEAP1 Promote Ferroptosis Protection and SCD1 Dependence in Lung Cancer', Cell Reports, vol. 33, no. 9, 108444. https://doi.org/10.1016/j.celrep.2020.108444

TY - JOUR

T1 - Concurrent Mutations in STK11 and KEAP1 Promote Ferroptosis Protection and SCD1 Dependence in Lung Cancer

AU - Wohlhieter, Corrin A.

AU - Richards, Allison L.

AU - Uddin, Fathema

AU - Hulton, Christopher H.

AU - Quintanal-Villalonga, Àlvaro

AU - Martin, Axel

AU - de Stanchina, Elisa

AU - Bhanot, Umeshkumar

AU - Asher, Marina

AU - Shah, Nisargbhai S.

AU - Hayatt, Omar

AU - Buonocore, Darren J.

AU - Rekhtman, Natasha

AU - Shen, Ronglai

AU - Arbour, Kathryn C.

AU - Donoghue, Mark

AU - Poirier, John T.

AU - Sen, Triparna

AU - Rudin, Charles M.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

KW - AKR1C1

KW - CRISPR

KW - KEAP1

KW - LKB1

KW - NSCLC

KW - SCD1

KW - STK11

KW - ferroptosis

UR - http://www.scopus.com/inward/record.url?scp=85097109925&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2020.108444

DO - 10.1016/j.celrep.2020.108444

M3 - Article

C2 - 33264619

AN - SCOPUS:85097109925

SN - 2211-1247

VL - 33

JO - Cell Reports

JF - Cell Reports

IS - 9

M1 - 108444

ER -

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

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Keywords

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