Clinicopathologic and Genomic Landscape of Non-Small Cell Lung Cancer Brain Metastases

Huang, Richard S.P.; Harries, Lukas; Decker, Brennan; Hiemenz, Matthew; Murugesan, Karthikeyan; Creeden, James; Tolba, Khaled A.; Stabile, Laura P.; Ramkissoon, Shakti; Burns, Timothy F.; Ross, Jeffrey S.

doi:10.1093/oncolo/oyac094

Cited by 23 publications

(18 citation statements)

References 34 publications

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“…Next, we analysed sequencing data of primary lung tumours and metastatic sites of NSCLC patients [ 39 ]. Confirming our in vitro observations and in line with a recently published study by Huang et al [ 40 ], we found that NKX2–1 amplifications are enriched in brain, lymph node and liver metastatic sites compared to the primary lung tumours (Fig. 5h ).…”

Section: Resultssupporting

confidence: 93%

Transcription factor NKX2–1 drives serine and glycine synthesis addiction in cancer

et al. 2023

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Background One-third of cancers activate endogenous synthesis of serine/glycine, and can become addicted to this pathway to sustain proliferation and survival. Mechanisms driving this metabolic rewiring remain largely unknown. Methods NKX2–1 overexpressing and NKX2–1 knockdown/knockout T-cell leukaemia and lung cancer cell line models were established to study metabolic rewiring using ChIP-qPCR, immunoblotting, mass spectrometry, and proliferation and invasion assays. Findings and therapeutic relevance were validated in mouse models and confirmed in patient datasets. Results Exploring T-cell leukaemia, lung cancer and neuroendocrine prostate cancer patient datasets highlighted the transcription factor NKX2–1 as putative driver of serine/glycine metabolism. We demonstrate that transcription factor NKX2–1 binds and transcriptionally upregulates serine/glycine synthesis enzyme genes, enabling NKX2–1 expressing cells to proliferate and invade in serine/glycine-depleted conditions. NKX2–1 driven serine/glycine synthesis generates nucleotides and redox molecules, and is associated with an altered cellular lipidome and methylome. Accordingly, NKX2–1 tumour-bearing mice display enhanced tumour aggressiveness associated with systemic metabolic rewiring. Therapeutically, NKX2–1-expressing cancer cells are more sensitive to serine/glycine conversion inhibition by repurposed anti-depressant sertraline, and to etoposide chemotherapy. Conclusion Collectively, we identify NKX2–1 as a novel transcriptional regulator of serine/glycine synthesis addiction across cancers, revealing a therapeutic vulnerability of NKX2–1-driven cancers.

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Section: Resultssupporting

confidence: 93%

Transcription factor NKX2–1 drives serine and glycine synthesis addiction in cancer

et al. 2023

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“…4A-C). Of note, the most prevalent genetic changes across all targetable somatic changes were EGFR, followed were CDKN2A and KRAS mutations, and the distribution of actionable mutation spectrum was similar to that in NSCLC cohort in some other study [26,27]. In our oligometastatic cohort, all the potential drugs targeting specific genetic alterations were also presented in Fig.…”

Section: A C C E P T E D a R T I C L E Korean Cancer Associationsupporting

confidence: 69%

Genomic Characteristics and the Potential Clinical Implications in Oligometastatic Non–Small Cell Lung Cancer

Liao¹,

Chen²,

Li³

et al. 2023

Cancer Res Treat

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Oligometastatic non-small cell lung cancer (NSCLC) patients have been increasingly regarded as a distinct group that could benefit from local treatment to achieve a better clinical outcome.However, current definitions of oligometastasis are solely numerical, which are imprecise because of ignoring the biological heterogeneity caused by genomic characteristics. Our study aimed to profile the molecular alterations of oligometastatic NSCLC and elucidate its potential difference from polymetastasis. Materials and MethodsWe performed next-generation sequencing (NGS) to analyze tumors and paired peripheral blood from 77 oligometastatic and 21 polymetastatic NSCLC patients to reveal their genomic characteristics and assess the genetic heterogeneity. ResultsWe found ERBB2, ALK, MLL4, PIK3CB and TOP2A were mutated at a significantly lower frequency in oligometastasis compared with polymetastasis. EGFR and KEAP1 alterations were mutually exclusive in oligometastatic group. More importantly, oligometastasis has a unique significant enrichment of apoptosis signaling pathway. In contrast to polymetastasis, a highly enriched COSMIC signature 4 and a special mutational process, COSMIC signature 14, were observed in the oligometastatic cohort. According to OncoKB database, 74.03% of oligometastatic NSCLC patients harbored at least one actionable alteration. The median tumor mutation burden (TMB) of oligometastasis was 5.00 mutations/Mb, which was significantly associated with smoking, DNA damage repair (DDR) genes, TP53 mutation, SMARCA4 mutation, LRP1B mutation, ABL1 mutation. Conclusion A c c e p t e d A r t i c l eCANCER RESEARCH AND TREATMENT (CRT) 3

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“…According to the results of univariate Cox analysis, the pathological T,N,M stages as well as brain metastasis are not factors related to survival whether the tumour exceeds 7 cm, with the presence or absence of pulmonary nodules’ and having proximal or distal metastasis. We chose to consider brain metastasis as an independent metastasis factor because shreds of evidence suggest that 20%–40% of LC patients will develop brain metastasis and 10% of non-small cells LC (NSCLC) patients are diagnosed with it at first LC discovery [ 24 – 26 ].…”

Section: Discussionmentioning

confidence: 99%

Lung cancer in middle and southern Morocco

Tafenzi¹,

Choulli²,

Baladi³

et al. 2023

ecancer

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Purpose Determining risk factors associated with a fatal disease such as lung cancer (LC) remains an important key to understanding the factors related to its development and therefore using the correct emergent or accessible treatments. For that, we sought to highlight by describing, and analysing, the risk factors related to LC survival, reflecting the actual situation in Morocco. Patients and methods We included 987 LC patients diagnosed from 2015 to 2021 at the Medical Oncology Department at the Mohammed VI University Hospital of Marrakech. An overview of the LC situation was described, and analysed, to determine the risk factors related to survival. The independent prognostic factors were determined using Cox Proportional Hazards Regression Analysis. To create a distinction between different risks group in the survival curve, stratification was done, respectively, within sex, age, histology type, treatments and radiation therapy. Results We finally included 862 patients with 15 parameters among the 27 extracted, all meeting the inclusion criteria. 89.1% of the patients were male ( n = 768) and 10.9% were female ( n = 94), of whom 83.5% had a history of tobacco smoking ( n = 720). The median survival of both sexes was 716 (5–2,167) days. The average age at diagnosis was 60 years. Five hundred and thirty-four patients presented with advanced stage. Patients above 66 years were the more diagnosed category with adenocarcinoma at T4N2M1c pathological category, and endocrinal comorbidity, in addition to pleurisy syndrome. Moreover, family history was found to be a bad prognostic factor. Interestingly, smoking status was not a bad contributor to survival. Age at diagnosis, histology subtype, performance status, haemoglobin, numbers of cures of the first-line chemotherapy, radiotherapy, anaemia and treatments were identified as risk factors related to survival. Conclusion We established a descriptive and analytical overview of the current LC epidemiology situation in the oncology division of Mohammed VI University Hospital in a non-industrialised state taking into account smoking status.

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Clinicopathologic and Genomic Landscape of Non-Small Cell Lung Cancer Brain Metastases

Cited by 23 publications

References 34 publications

Transcription factor NKX2–1 drives serine and glycine synthesis addiction in cancer

Transcription factor NKX2–1 drives serine and glycine synthesis addiction in cancer

Genomic Characteristics and the Potential Clinical Implications in Oligometastatic Non–Small Cell Lung Cancer

Lung cancer in middle and southern Morocco

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