4.8 Article

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

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NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -

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NATURE RESEARCH
DOI: 10.1038/s41467-021-22336-4

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资金

  1. Erasmus Fellowship by the European Union
  2. Max-Eder-Junior Research Group grant by the German Cancer Aid, a project grant [701125509, 432038712]
  3. German Research Foundation (Deutsche Forschungsgesellschaft, DFG) [SFB1399, SFB1403, EXC 2030-390661388]
  4. German state (BMBF) [01ZX1901A]
  5. center for molecular medicine (CMMC), Cologne, Germany
  6. Thyssen Foundation [10.19.2.025MN]
  7. German Cancer Aid [70112888]

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The loss of TP53 and RB1 in treatment-naive small cell lung cancer (SCLC) indicates a need to inactivate cell death pathways prior to therapy. This study identifies non-neuroendocrine (NE) SCLC as vulnerable to ferroptosis and neuroendocrine (NE) SCLC as susceptible to TRX pathway inhibition, with combining these treatments showing promise in overcoming subtype plasticity in SCLC.
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.

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