Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes

被引：104

作者：

Bebber, Christina M. ^{[1
,2
,3
]}

Thomas, Emily S. ^{[1
,2
,4
]}

Stroh, Jenny ^{[1
,2
]}

Chen, Zhiyi ^{[1
,2
]}

Androulidaki, Ariadne ^{[1
,2
]}

Schmitt, Anna ^{[2
,3
]}

Hoehne, Michaela N. ^{[2
,5
]}

Stueker, Lukas ^{[1
,2
]}

Alves, Cleidson de Padua ^{[1
]}

Khonsari, Armin ^{[1
,6
,7
]}

Dammert, Marcel A. ^{[1
,6
,7
]}

Parmaksiz, Fatma ^{[1
,6
,7
]}

Tumbrink, Hannah L. ^{[1
,6
,7
]}

Beleggia, Filippo ^{[3
]}

Sos, Martin L. ^{[1
,6
,7
]}

Riemer, Jan ^{[2
,5
]}

George, Julie ^{[1
]}

Brodesser, Susanne ^{[2
]}

Thomas, Roman K. ^{[1
,6
,8
]}

Reinhardt, H. Christian ^{[9
,10
]}

von Karstedt, Silvia ^{[1
,2
,7
]}

机构：

[1] Univ Cologne, Fac Med, Dept Translat Genom, Cologne, Germany

[2] Univ Cologne, CECAD Cluster Excellence, Cologne, Germany

[3] Univ Hosp Cologne, Fac Med, Clin Internal Med, Cologne, Germany

[4] Imperial Coll London, London, England

[5] Univ Cologne, Inst Biochem, Dept Chem, Cologne, Germany

[6] Univ Hosp Cologne, Fac Med, Inst Pathol, Cologne, Germany

[7] Univ Hosp Cologne, Ctr Mol Med Cologne, Fac Med, Cologne, Germany

[8] German Canc Consortium DKTK, German Canc Res Ctr, Heidelberg, Germany

[9] Univ Hosp Essen, Dept Hematol & Stem Cell Transplantat, Essen, Germany

[10] Univ Duisburg Essen, German Canc Consortium DKTK partner site Essen, Essen, Germany

来源：

NATURE COMMUNICATIONS | 2021年 / 12卷 / 01期

关键词：

MIXED LINEAGE KINASE; LIPID-METABOLISM; DOMAIN-LIKE; IDENTIFICATION; DEATH; TRAIL; INACTIVATION; GLUTATHIONE; EXPRESSION; CASPASE-8;

D O I：

10.1038/s41467-021-22336-4

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Loss of TP53 and RB1 in treatment-naive small cell lung cancer (SCLC) suggests selective pressure to inactivate cell death pathways prior to therapy. Yet, which of these pathways remain available in treatment-naive SCLC is unknown. Here, through systemic analysis of cell death pathway availability in treatment-naive SCLC, we identify non-neuroendocrine (NE) SCLC to be vulnerable to ferroptosis through subtype-specific lipidome remodeling. While NE SCLC is ferroptosis resistant, it acquires selective addiction to the TRX anti-oxidant pathway. In experimental settings of non-NE/NE intratumoral heterogeneity, non-NE or NE populations are selectively depleted by ferroptosis or TRX pathway inhibition, respectively. Preventing subtype plasticity observed under single pathway targeting, combined treatment kills established non-NE and NE tumors in xenografts, genetically engineered mouse models of SCLC and patient-derived cells, and identifies a patient subset with drastically improved overall survival. These findings reveal cell death pathway mining as a means to identify rational combination therapies for SCLC. The high degree of subtype plasticity in small cell lung cancer (SCLC) poses a therapeutic challenge. Here, the authors show that the non-neuroendocrine (non-NE) subtype of SCLC is sensitive to ferroptosis while the neuroendocrine (NE) subtype is vulnerable to TRX anti-oxidant pathway inhibition, and the combination of these two treatments in SCLC circumvents non-NE/NE subtype plasticity.

引用

页数：19

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