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

Abstract

Bi-allelic loss of TP53 and RB1 in treatment-naïve small cell lung cancer (SCLC) suggests strong selective pressure to inactivate regulated cell death pathways prior to therapy. Yet, which regulated cell death pathways remain available in treatment-naïve SCLC is unknown. Here, through systemic analysis of cell death pathway availability, we identify non-neuroendocrine (NE) and NE SCLC subtypes to segregate by their response to ferroptosis, a recently described iron-dependent type of regulated necrosis. While we identify that in treatment-naïve SCLC extrinsic apoptosis and necroptosis are incapacitated, we find non-NE SCLC to be exquisitely sensitive to ferroptosis induced through pharmacological and genetic means. Mechanistically, non-NE SCLC as opposed to NE SCLC presents with an oxygenated lipidome priming non-NE SCLC for ferroptosis. ASCL1+ NE SCLC, in turn, is resistant to ferroptosis but acquires selective addiction to the thioredoxin (TRX) anti-oxidant pathway. Importantly, co-cultures mimicking non-NE/NE intratumoral heterogeneity selectively deplete non-NE populations upon induction of ferroptosis while eliminating NE cell populations only upon TRX pathway. As a consequence, combined induction of ferroptosis and inhibition of the TRX pathway broadly kills established non-NE and NE tumors in xenografts and genetically engineered mouse models of SCLC. Moreover, patient-derived treatment-naïve and refractory NE SCLC models are selectively killed via this regime. In SCLC, combined low expression of GPX4 and TRX reductase 1 (TXNRD1) identifies a patient subset with drastically improved overall survival. These data identify ferroptosis as an SCLC subtype-specific vulnerability and suggest repurposing ferroptosis induction with TRX pathway inhibition to specifically address intratumoral NE/non-NE heterogeneity in SCLC.One Sentence SummaryThe SCLC non-neuroendocrine subtype is sensitive to ferroptosis

Molecular profiles of small cell lung cancer subtypes: Therapeutic implications

“…Recent data described an iron-dependent type of regulated necrosis called ferroptosis. 134 Non-NE SCLCs were demonstrated to be selectively sensitive to induced ferroptosis. 134 In contrast, high-NE SCLCs are resistant to induced ferroptosis, but respond exquisitely to thioredoxin (TRX) pathway inhibition.…”

“…134 Non-NE SCLCs were demonstrated to be selectively sensitive to induced ferroptosis. 134 In contrast, high-NE SCLCs are resistant to induced ferroptosis, but respond exquisitely to thioredoxin (TRX) pathway inhibition. 134 A combination of ferroptosis induction and TRX pathway inhibition may thus provide a treatment regimen for intratumoral NE/non-NE heterogeneous SCLC.…”

“…134 In contrast, high-NE SCLCs are resistant to induced ferroptosis, but respond exquisitely to thioredoxin (TRX) pathway inhibition. 134 A combination of ferroptosis induction and TRX pathway inhibition may thus provide a treatment regimen for intratumoral NE/non-NE heterogeneous SCLC. 134 Open questions What is the clinical relevance of intratumoral and intertumoral heterogeneity in SCLC?…”

“…134 A combination of ferroptosis induction and TRX pathway inhibition may thus provide a treatment regimen for intratumoral NE/non-NE heterogeneous SCLC. 134 Open questions What is the clinical relevance of intratumoral and intertumoral heterogeneity in SCLC?…”

“…Ferroptosis and arginine depletion have recently been investigated to become targets for subtype-specific therapy. 54,134 MYC-driven SCLC cells are dependent on different arginine-regulated pathways. 54 Non-NE SCLCs are reported to be specifically sensitive to induced ferroptosis.…”