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| Open AccessMitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC
The relevance of mitochondrial cysteine metabolism to ferroptosis is unknown. Here, Ward et al. show that mitochondrial Fe-S cluster synthesis persists under cysteine limitation via the catabolism of glutathione and at the expense of cell viability.
- Nathan P. Ward
- , Sang Jun Yoon
- & Gina M. DeNicola
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Article
| Open AccessFerritinophagy mediates adaptive resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer
The mechanisms leading to acquired resistance to targeted therapy in cancer are not completely understood. Here, the authors show that ferritinophagy mediates adaptive resistance to Osimertinib, and that combining this EGFR tyrosine kinase inhibitor with copper ionophores improves its therapeutic efficacy in preclinical models of non-small cell lung cancer.
- Hui Wang
- , Qianfan Hu
- & Feng Jiang
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Article
| Open AccessFocal adhesion kinase-YAP signaling axis drives drug-tolerant persister cells and residual disease in lung cancer
Remaining drug-tolerant persistent (DTP) cancer cells limit the efficacy of targeted therapy in EGFR, ALK and KRAS mutant non-small cell lung cancer (NSCLC). Here, the authors show that focal adhesion kinase (FAK)-YAP signalling supports DTP cells promoting residual disease and targeting this pathway improved tumour response in NSCLC preclinical models.
- Franziska Haderk
- , Yu-Ting Chou
- & Trever G. Bivona
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Article
| Open AccessEnhancing NSCLC recurrence prediction with PET/CT habitat imaging, ctDNA, and integrative radiogenomics-blood insights
Predicting recurrence risk in non small cell lung cancer can help to guide treatment decisions. Here, the authors use CT and PET imaging to develop predictive imaging subtypes, which can be integrated with existing ctDNA methods to predict recurrence.
- Sheeba J. Sujit
- , Muhammad Aminu
- & Jia Wu
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Article
| Open AccessComprehensive mutational scanning of EGFR reveals TKI sensitivities of extracellular domain mutants
EGFR mutations are frequent in glioblastoma and lung cancer. Here, the authors perform deep mutational scanning of EGFR, followed by a high-throughput functional screen and analysis of patient data, to identify variants with differing sensitivities to a range of EGFR tyrosine kinase inhibitors.
- Tikvah K. Hayes
- , Elisa Aquilanti
- & Matthew Meyerson
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Article
| Open AccessPolygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis
Colitis is one of the most common immune-related adverse events in patients with cancer treated with immune checkpoint inhibitors. Here the authors show that a polygenic risk score for ulcerative colitis can predict immune checkpoint inhibitor-mediated colitis in patients with cancer.
- Pooja Middha
- , Rohit Thummalapalli
- & Elad Ziv
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Article
| Open AccessOutcome differences by sex in oncology clinical trials
The role of sex differences in response to cancer therapy remains unclear but this could be improved by reporting sex comparisons of outcomes in clinical trials. Here, the authors characterise the sex outcome comparisons in 89,221 interventional trials, finding that while comparisons were rare, important insights could be obtained.
- Ashwin V. Kammula
- , Alejandro A. Schäffer
- & Eytan Ruppin
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Article
| Open AccessBET inhibitors drive Natural Killer activation in non-small cell lung cancer via BRD4 and SMAD3
Combination of BET inhibitors (BETi) with immunotherapy has been reported to be synergic for the treatment of non-small cell lung carcinoma (NSCLC). Here, the authors show that BETi-induced epigenetic reprogramming downregulates the expression of NK cell inhibitory receptors on NK cells, increasing their activation and cytotoxicity against NSCLC.
- Francesca Reggiani
- , Giovanna Talarico
- & Valentina Sancisi
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Article
| Open AccessGAS41 modulates ferroptosis by anchoring NRF2 on chromatin
GAS41 is recognized as a histone reader and oncogene, but the mechanism by which GAS41 contributes to tumorigenesis is not well understood. Here, the authors discover that GAS41 is a ferroptosis repressor that anchors NRF2 to chromatin, promoting tumor growth.
- Zhe Wang
- , Xin Yang
- & Wei Gu
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Article
| Open AccessDrug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers
The Epidermal Growth Factor Receptor (EGFR) is frequently found to be mutated in non-small cell lung cancer. Here, the authors show that EGFR lung cancer mutations promote the assembly of kinase-active dimers within ligand-free EGFR oligomers. These dimers bind ligand with high affinity and promote tumor growth.
- R. Sumanth Iyer
- , Sarah R. Needham
- & Marisa L. Martin-Fernandez
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Article
| Open AccessDendritic cell-targeted therapy expands CD8 T cell responses to bona-fide neoantigens in lung tumors
Response to immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC) remains suboptimal, even for tumors with elevated tumor mutational burden. Here the authors generate a model of NSCLC with enhanced mutational load, showing that, while still resistant to ICIs, hypermutated tumors become sensitive to dendritic cell-targeted therapy.
- Lucía López
- , Luciano Gastón Morosi
- & Federica Benvenuti
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Article
| Open AccessA SWI/SNF-dependent transcriptional regulation mediated by POU2AF2/C11orf53 at enhancer
POU2AF2 is a co-activator of POU2F3 in normal and neoplastic tuft cells, such as small cell lung cancer. Here, the authors report that POU2AF2 dictates opposing transcriptional regulation at distal enhance elements.
- Aileen Szczepanski
- , Natsumi Tsuboyama
- & Lu Wang
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Article
| Open AccessA Phase II trial of alternating osimertinib and gefitinib therapy in advanced EGFR-T790M positive non-small cell lung cancer: OSCILLATE
Alterations of therapeutic pressures have been shown to affect clonal evolution of resistance. Here, the authors conducted a single arm, phase 2 trial consisting of alternating osimertinib and gefitinib in non-small cell lung cancer, and found ctDNA dynamics were predictive of response.
- Lavinia Tan
- , Chris Brown
- & Benjamin J. Solomon
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Article
| Open AccessSintilimab with two cycles of chemotherapy for the treatment of advanced squamous non-small cell lung cancer: a phase 2 clinical trial
Combining standard 4-6 cycles of chemotherapy with immune checkpoints inhibitors has shown to improve survival in patients with non-small cell lung cancer (NSCLC), however increased toxicities have also been reported. Here the authors report the results of a phase 2 trial of sintilimab (anti-PD1) with two cycles of chemotherapy for treatment of previously untreated advanced squamous NSCLC.
- Mina Zhang
- , Guowei Zhang
- & Huijuan Wang
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Article
| Open AccessUPP1 promotes lung adenocarcinoma progression through the induction of an immunosuppressive microenvironment
Characterising the tumour microenvironment features of lung adenocarcinoma (LUAD) remains crucial. Here, the authors perform single cell RNA sequencing data analysis of 117 LUAD samples and functional assays and highlight the immunosuppressive role of UPP1high tumour cells.
- Yin Li
- , Manling Jiang
- & Chunlai Lu
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Article
| Open AccessNeoadjuvant durvalumab plus radiation versus durvalumab alone in stages I–III non-small cell lung cancer: survival outcomes and molecular correlates of a randomized phase II trial
The authors previously reported the primary outcomes of a randomized phase II trial comparing neoadjuvant durvalumab (anti-PD-L1) alone or in combination with stereotactic radiotherapy in patients with early-stage NSCLC. Here, the authors report the secondary outcomes of the trial and post hoc analysis.
- Nasser K. Altorki
- , Zachary H. Walsh
- & Timothy E. McGraw
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Article
| Open AccessWhole-genome sequencing reveals the molecular implications of the stepwise progression of lung adenocarcinoma
Current sequencing technologies can shed light on the stepwise progression of lung adenocarcinoma. Here, the authors characterize tumor progression in lung adenocarcinomas from an early stage using short and long read whole-genome sequencing, bulk and spatial transcriptomics, and epigenomics.
- Yasuhiko Haga
- , Yoshitaka Sakamoto
- & Ayako Suzuki
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Article
| Open AccessNanomedicine-based co-delivery of a calcium channel inhibitor and a small molecule targeting CD47 for lung cancer immunotherapy
Lung cancer is characterized by an immunosuppressive microenvironment, limiting responses to immunotherapies. Here the authors report the design of a pH-responsive nanomedicine for the co-delivery of a T-type calcium channel inhibitor and of a small molecule targeting CD47, promoting anti-tumor immune responses in orthotopic lung cancer preclinical models.
- Yuedong Guo
- , Qunqun Bao
- & Jianlin Shi
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Article
| Open AccessDostarlimab or pembrolizumab plus chemotherapy in previously untreated metastatic non-squamous non-small cell lung cancer: the randomized PERLA phase II trial
Several PD-(L)1 inhibitors have been approved or are in development for the treatment of NSCLC, showing promising efficacy and tolerable safety profiles. Here, the authors present a randomized phase II clinical trial comparing two different anti-PD-1 antibodies, dostarlimab and pembrolizumab, both combined with chemotherapy as first-line treatment in patients with metastatic NSCLC.
- Sun Min Lim
- , Solange Peters
- & Filippo de Marinis
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Article
| Open AccessInflammation in the tumor-adjacent lung as a predictor of clinical outcome in lung adenocarcinoma
Lung adenocarcinoma is often curable when diagnosed at an early stage, but a subsection of patients will progress. Here, the authors use multi-omics profiling to show that gene expression data can predict clinical outcome.
- Igor Dolgalev
- , Hua Zhou
- & Aristotelis Tsirigos
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Article
| Open AccessSelective activator of human ClpP triggers cell cycle arrest to inhibit lung squamous cell carcinoma
Chemo-activation of mitochondrial ClpP exhibits promising anticancer properties. Here, the authors develop a potent activator ZK53 that is highly selective on human ClpP but inactive toward bacterial ClpP proteins, and show that ZK53 causes cell cycle arrest via ClpP on lung squamous cell carcinoma cells and exhibits therapeutic effects in animal models.
- Lin-Lin Zhou
- , Tao Zhang
- & Cai-Guang Yang
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Article
| Open AccessGlycerol-weighted chemical exchange saturation transfer nanoprobes allow 19F/1H dual-modality magnetic resonance imaging-guided cancer radiotherapy
Radiotherapy (RT) sensitizers have been used to overcome tumor hypoxia and improve response to RT. Here the authors design and characterize a pH and oxygen sensitive nano-molecular probe for imaging-guided cancer radiotherapy.
- Rong A
- , Haoyu Wang
- & Xilin Sun
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Article
| Open AccessSignature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer
The success of targeting KRAS for cancer therapy is limited by resistance due to compensatory mechanism, making combinatorial approaches attractive. Here, the authors use a KRAS signature drug repurposing screen and identify the multityrosine kinase PKC inhibitor Midostaurin as synergistic with MEK and KRAS inhibitors in KRAS-mutated lung adenocarcinoma.
- Irati Macaya
- , Marta Roman
- & Silve Vicent
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Article
| Open AccessYAP silencing by RB1 mutation is essential for small-cell lung cancer metastasis
Small cell lung cancers (SCLC) have often inactivating mutations in RB1. In this study, the authors demonstrate that RB1 loss mediates low expression of YAP1 in SCLC tumors ultimately promoting metastasis and they propose to use benzamide family HDAC inhibitors to induce YAP1 expression for prevention of metastases.
- Zhengming Wu
- , Junhui Su
- & Kun-Liang Guan
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Article
| Open AccessCritical requirement of SOS1 for tumor development and microenvironment modulation in KRASG12D-driven lung adenocarcinoma
Critical regulators of RAS signaling pathways in oncogenic RAS-driven tumors remain to be explored. Here, the authors show the development of KRAS(G12D)-driven lung adenocarcinoma is dependent on SOS1, with dual roles in both tumor and stroma.
- Fernando C. Baltanás
- , Rósula García-Navas
- & Eugenio Santos
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| Open AccessAtezolizumab plus stereotactic ablative radiotherapy for medically inoperable patients with early-stage non-small cell lung cancer: a multi-institutional phase I trial
Stereotactic ablative radiotherapy (SABR) is standard-of-care for patients with medically inoperable early-stage non-small cell lung cancer (NSCLC), however the risk of systemic recurrences remains high. Here the authors report the results of a phase I study testing the addition of atezolizumab (anti-PD-L1) to SABR in high risk, medically inoperable, early-stage, NSCLC.
- Arta M. Monjazeb
- , Megan E. Daly
- & Karen Kelly
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Article
| Open AccessAcquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype
Acquired resistance to immune checkpoint inhibitors limits therapeutic success in non-small-cell lung cancer, however, the underpinning immune parameters are largely unknown. Here authors distinguish resistance types based on immune cell infiltration, immune checkpoint molecule and cytokine expression level, using paired samples from patients in the sensitive and in the resistant disease phase.
- Stefanie Hiltbrunner
- , Lena Cords
- & Alessandra Curioni-Fontecedro
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Article
| Open AccessLongitudinal high-dimensional analysis identifies immune features associating with response to anti-PD-1 immunotherapy
Immune checkpoint blockade therapy improved the survival rates of non-small cell lung cancer but only a proportion of patients benefit. Here authors follow the humoral and cellular immunological parameters of patients undergoing anti-PD1 therapy longitudinally and find that levels and functional properties of cytotoxic T cells, and especially CD8+CD101hiTIM3+ cells determine the response.
- Elaine Lai-Han Leung
- , Run-Ze Li
- & Liang Liu
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Article
| Open AccessGenomic analysis and clinical correlations of non-small cell lung cancer brain metastasis
The genomic landscape of brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC) remains to be explored. Here, the authors analyse a cohort of 233 patients with BM including 47 primary tumour, 42 extracranial metastatic matched samples and reveal distinct mutational patterns.
- Anna Skakodub
- , Henry Walch
- & Luke R. G. Pike
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Article
| Open AccessNeoadjuvant Afatinib for stage III EGFR-mutant non-small cell lung cancer: a phase II study
Afatinib is a second-generation EGFR tyrosine kinase inhibitor recommended as the first-line treatment for patients with advanced EGFR mutant non-small cell lung cancer (NSCLC). Here the authors report the results of a phase II clinical trial of neoadjuvant afatinib for stage III EGFR mutant NSCLC.
- Dongliang Bian
- , Liangdong Sun
- & Peng Zhang
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Article
| Open Accessp53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism
p53 inactivation is nearly universal in small-cell lung cancer (SCLC), but its tumor suppressive role in this cancer type is poorly understood. Here the authors show that intertumoral heterogeneity in SCLC influences the biological mechanisms of p53-mediated tumor suppression and identify a role for cyclophilins in p53-dependent necrotic cell death.
- Jonuelle Acosta
- , Qinglan Li
- & David M. Feldser
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Article
| Open AccessImpact of TMB/PD-L1 expression and pneumonitis on chemoradiation and durvalumab response in stage III NSCLC
Concurrent chemoradiation and durvalumab is standard of care for stage III non-small cell lung cancer, however, efficacy is variable. Here, the authors show PD-L1 tumor proportion score expression and increased tumor mutational burden are predictive of response and that early-onset pneumonitis leading to durvalumab discontinuation is associated with poor survival.
- Joao V. Alessi
- , Biagio Ricciuti
- & Narek Shaverdian
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Article
| Open AccessUHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma
Identifying KRAS-specific vulnerabilities helps to target KRAS-driven cancer. Here the authors perform RNA interference screens in 3D cultures of primary tumour cells with KRAS activation and p53 loss and identify UHRF1 as a vulnerability of KRAS-mutant lung cancers
- Kaja Kostyrko
- , Marta Román
- & E. Alejandro Sweet-Cordero
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Article
| Open AccessA landscape of response to drug combinations in non-small cell lung cancer
Combination of drugs within cancer treatment is a popular way to overcome resistance and increase efficacy. Here, the authors analyse over 5000 targeted agent combinations in non-small cell lung cancer to identify potentially effective drug strategies.
- Nishanth Ulhas Nair
- , Patricia Greninger
- & Cyril H. Benes
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Article
| Open AccessPhase 1b trial of anti-EGFR antibody JMT101 and Osimertinib in EGFR exon 20 insertion-positive non-small-cell lung cancer
Patients with non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions are resistant to early generation EGFR tyrosine kinase inhibitors (TKI). Here, the authors report the safety and preliminary efficacy of a phase I clinical trial JMT101, an anti-EGFR antibody, combined with EGFR-TKI, afatinib or osimertinib, in patients with NSCLC.
- Shen Zhao
- , Wu Zhuang
- & Wenfeng Fang
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Article
| Open AccessNOTCH4ΔL12_16 sensitizes lung adenocarcinomas to EGFR-TKIs through transcriptional down-regulation of HES1
Patients with lung adenocarcinoma (LUAD) patients carrying EGFR mutations are often treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs), but sensitivity to the therapy varies. Here, using 3D printed patient derived xenograft models, the authors identify a NOTCH mutation as an indicator of favourable response to EGFR-TKI in LUAD.
- Bin Zhang
- , Shaowei Dong
- & Chang Zou
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Article
| Open AccessThe blood proteome of imminent lung cancer diagnosis
Lung cancer screening could enhance early diagnosis and treatment. Here, the authors used proteomic analysis of pre-diagnosis samples across 6 cohorts to identify 36 proteins associated with imminent lung cancer diagnosis.
- Demetrius Albanes
- , Karine Alcala
- & Wei Zheng
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Article
| Open AccessIn vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer
There is still a limited understanding of mechanisms of sensitivity/resistance to cancer immunotherapy. Here the authors perform in vivo CRISPR/Cas9 loss-of-function screens in mouse lung cancer models, revealing Serpinb9 and Adam2 as regulators of immunotherapy response.
- Dzana Dervovic
- , Ahmad A. Malik
- & Daniel Schramek
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Article
| Open AccessImmune cellular patterns of distribution affect outcomes of patients with non-small cell lung cancer
The spatial distribution of cellular compartments within the tumour microenvironment in non-small cell lung cancer (NSCLC) remains to be investigated. Here, the authors identify distinct cell populations of tumour cells and tumour-associated immune cell phenotypes with different spatial distributions in NSCLC.
- Edwin Roger Parra
- , Jiexin Zhang
- & Ignacio Ivan Wistuba
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Article
| Open AccessCDK4/6 inhibition triggers ICAM1-driven immune response and sensitizes LKB1 mutant lung cancer to immunotherapy
LKB1 mutations have been associated with primary resistance to immune checkpoint inhibitors in patients with lung cancer. Here the authors show that Lkb1-deficient lung tumors are characterized by defective trafficking and adhesion of T cells and that, by upregulating ICAM1 expression, CDK4/6 inhibitors sensitize LKB1 mutant lung cancer to anti-PD1 blockade.
- Xue Bai
- , Ze-Qin Guo
- & Zhong-Yi Dong
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Article
| Open AccessCandidate mechanisms of acquired resistance to first-line osimertinib in EGFR-mutated advanced non-small cell lung cancer
In the phase III FLAURA study (NCT02296125), the third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib provided superior progression-free survival versus comparator EGFR-TKIs in patients with NSCLC. Here, by next-generation sequencing of circulating tumor DNA, the authors assess candidate mechanisms of acquired resistance to first-line osimertinib in patients from the FLAURA trial.
- Juliann Chmielecki
- , Jhanelle E. Gray
- & Suresh S. Ramalingam
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Article
| Open AccessAnalysis of acquired resistance mechanisms to osimertinib in patients with EGFR-mutated advanced non-small cell lung cancer from the AURA3 trial
In the phase III AURA3 study (NCT02151981), the third-generation epidermal growth factor receptor tyrosine kinase inhibitor osimertinib prolonged progression-free survival versus platinum-doublet chemotherapy in patients with EGFR T790M advanced NSCLC. Here, by next-generation sequencing of circulating tumor DNA, the authors assess candidate mechanisms of acquired resistance to osimertinib in patients from the AURA3 trial.
- Juliann Chmielecki
- , Tony Mok
- & Vassiliki Papadimitrakopoulou
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Article
| Open AccessEfficacy and clinicogenomic correlates of response to immune checkpoint inhibitors alone or with chemotherapy in non-small cell lung cancer
Immune checkpoint inhibitors with or without chemotherapy are now standard of care for non-small cell lung cancer. However, the benefits of combination vs sequential therapy have not been fully explored. Here, the authors analysed 1,133 patient records and show combination therapy showed increased protection against early progression, but similar overall survival.
- Lingzhi Hong
- , Muhammad Aminu
- & Natalie I. Vokes
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Article
| Open AccessSingle-cell analysis reveals prognostic fibroblast subpopulations linked to molecular and immunological subtypes of lung cancer
Fibroblast heterogeneity is a prominent but poorly understood feature of solid tumours. Here three major fibroblast subpopulations in non-small cell lung cancer are identified and characterised through single cell RNA-sequencing, multiplexed immunohistochemistry and digital cytometry.
- Christopher J. Hanley
- , Sara Waise
- & Gareth J. Thomas
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Article
| Open AccessIn vivo induction of activin A-producing alveolar macrophages supports the progression of lung cell carcinoma
Alveolar macrophages represent a cell type that is physiologic to the lung immune landscape, however, it is not known whether they play an active role to maintain the tumour immune microenvironment. Here authors show by single cell RNA sequencing and functional experiments, that intra-tumour alveolar macrophages are phenotypically and transcriptionally different from the healthy ones, and likely play an aetio-pathologic role in tumorigenesis.
- Seiji Taniguchi
- , Takahiro Matsui
- & Masaru Ishii
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Article
| Open AccessTumor-intrinsic IRE1α signaling controls protective immunity in lung cancer
The IRE1α-XBP1 arm of the unfolded protein response (UPR) has been associated with immunosuppression and cancer progression. Here the authors show that IRE1α-XBP1 activation is associated with poor overall survival in patients with non-small cell lung cancer and that IRE1α loss in cancer cells promotes anti-tumor immune responses in lung cancer preclinical models.
- Michael J. P. Crowley
- , Bhavneet Bhinder
- & Vivek Mittal
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Article
| Open AccessUSP5-Beclin 1 axis overrides p53-dependent senescence and drives Kras-induced tumorigenicity
Oncogene-induced senescence (OIS) occurs in premalignant lung adenomas, but infrequently in malignant adenocarcinomas. Here the authors show that USP5-Beclin 1 axis overcomes OIS in Kras-driven lung cancer by enhancing MDM2-mediated p53 degradation.
- Juan Li
- , Yang Wang
- & Zhi-Xiong Jim Xiao
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Article
| Open AccessA fluorogenic probe for predicting treatment response in non-small cell lung cancer with EGFR-activating mutations
The presence of activating epidermal growth factor receptor (EGFR) mutations in patients with lung cancer correlates to improved response to EGFR-tyrosine kinase inhibitors. Here, the authors present a fluorescence-activated cell sorting assay to identify EGFR mutations with functional activity in patients and demonstrate its utility in predicting response to EGFR-TKI.
- Hui Deng
- , Qian Lei
- & Weimin Li
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Article
| Open AccessBiochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations
Although small molecule tyrosine kinase inhibitors are effective in lung cancer driven by mutated EGFR, some receptor variants fail to respond. Here, the authors identify structural features of an important set of EGFR variants with reduced inhibitor sensitivity, guiding future inhibitor selection.
- Iris K. van Alderwerelt van Rosenburgh
- , David M. Lu
- & Yuko Tsutsui