Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma

Hu, Kewen; Li, Kun; Lv, Jing; Feng, Jie; Chen, Jing; Wu, Haigang; Cheng, Feixiong; Jiang, Wenhao; Wang, Jieqiong; Pei, Haixiang; Chiao, Paul J.; Cai, Zhenyu; Chen, Yihua; Liu, Mingyao; Pang, Xiufeng

doi:10.1172/jci124049

Cited by 234 publications

(214 citation statements)

References 57 publications

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“…Solute carrier family 7 member 11 (SLC7A11) is the functional light chain subunit of the cystine/glutamate antiporter system and participates in the cystine uptake specificity [54].…”

Section: Down-regulated Genes In Laying Hens With Dbementioning

confidence: 99%

Transcriptomic analysis of the liver in aged laying hens with different intensity of brown eggshell color

et al. 2021

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Objective: Eggshell color is an important indicator of egg quality for consumers, especially for brown eggs. Various factors related to laying hens and their environment affect brown eggshell coloration. However, there have been no studies investigating hepatic functions of laying hens with variable intensity of brown eggshell color. Therefore, this study was aimed to identify potential factors affecting brown eggshell coloration in aged laying hens at the hepatic transcriptomic level. Methods: Five hundred 92-wk-old Hy-line Brown laying hens were screened to select laying hens with different intensity of brown eggshell color based on eggshell color fans. Based on eggshell color scores, hens with dark brown eggshells (DBE; eggshell color fan score = 14.8) and hens with light brown eggshells (LBE; eggshell color fan score = 9.7) were finally selected for the liver sampling. We performed RNA-seq analysis using the liver samples through the paired-end sequencing libraries. Differentially expressed genes (DEGs) profiling was carried out to identify their biological meaning by bioinformatics. Results: A total of 290 DEGs were identified with 196 being up-regulated and 94 being down-regulated in DBE groups as compared to LBE groups. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that these DEGs belong to several biological pathways including herpes simplex infection (TLR3, TAP2, TAP1, CDK1, etc.) and influenza A (TLR3, RSAD2, MX1, etc.). Genes related to stress response (CERKL) and nutrient A c c e p t e d A r t i c l e 3 metabolism (PCK1, MMAB, GLRA2, SLC7A11, etc.) were also identified to be differentially expressed. Conclusion: The current results provide new insights regarding hepatic molecular functions related to different intensity of brown eggshell color in aged laying hens. These insights will contribute to future studies aiming to optimize brown eggshell coloration in aged laying hens.

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“…Solute carrier family 7 member 11 (SLC7A11) is the functional light chain subunit of the cystine/glutamate antiporter system and participates in the cystine uptake specificity [54].…”

Section: Down-regulated Genes In Laying Hens With Dbementioning

confidence: 99%

Transcriptomic analysis of the liver in aged laying hens with different intensity of brown eggshell color

et al. 2021

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“… A549, H226, HL7702 A549 xenograft mouse Lung cancer [ 48 ] KRAS 12p12.1 Transcriptional activator that regulates endothelial cells endothelin-1 gene expression. A549, H441 A549 xenograft mouse Lung cancer [ 49 , 50 ] MRE11 11q21 MRN complex component; DNA double-strand breaks repair via nonhomologous end-joining and homologous recombination activation in ATM-mediated checkpoint. V-C8 N/A N/A [ 51 ] MYC 8q24.21 Regulate cell cycle progression, transcription, and apoptosis.…”

Section: Synthetic Lethal Mechanismmentioning

confidence: 99%

Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation

et al. 2020

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Synthetic lethality is a lethal phenomenon in which the occurrence of a single genetic event is tolerable for cell survival, whereas the co-occurrence of multiple genetic events results in cell death. The main obstacle for synthetic lethality lies in the tumor biology heterogeneity and complexity, the inadequate understanding of synthetic lethal interactions, drug resistance, and the challenges regarding screening and clinical translation. Recently, DNA damage response inhibitors are being tested in various trials with promising results. This review will describe the current challenges, development, and opportunities for synthetic lethality in cancer therapy. The characterization of potential synthetic lethal interactions and novel technologies to develop a more effective targeted drug for cancer patients will be explored. Furthermore, this review will discuss the clinical development and drug resistance mechanisms of synthetic lethality in cancer therapy. The ultimate goal of this review is to guide clinicians at selecting patients that will receive the maximum benefits of DNA damage response inhibitors for cancer therapy.

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“…Thereby, inactivation of extrinsic apoptosis can in principle cross-activate necroptosis. Interestingly, induction of ferroptosis-a recently coined type of regulated necrosis-was shown to selectively kill KRASdriven pancreatic and lung cancer representing a novel therapeutic vulnerability in these cancers (13,14). Yet, whether SCLC, which is almost never KRAS-mutated, might respond to induction of ferroptosis has remained unexplored.…”

Section: Introductionmentioning

confidence: 99%

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

Bebber

Thomas

Chen

et al. 2020

Preprint

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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

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Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma

Cited by 234 publications

References 57 publications

Transcriptomic analysis of the liver in aged laying hens with different intensity of brown eggshell color

Transcriptomic analysis of the liver in aged laying hens with different intensity of brown eggshell color

Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation

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

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