Genomic alterations in small cell lung cancer and their clinical relevance

Wildey, Gary; Dowlati, Afshin

doi:10.21037/tlcr.2016.07.05

Cited by 3 publications

(2 citation statements)

References 10 publications

(8 reference statements)

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“…Unlike NSCLC, SCLC is characterized by universal loss of RB1 and TP53 and traditionally diagnosed, classified, and treated as a single disease (Table 1) (51,(61)(62)(63)(64). The evolution of SCLC subtyping has occurred over the past 30 years starting with the observation that SCLC cell lines had two prominent biochemical signatures, which resulted in classification of classical and variant subtypes (65).…”

Section: Small Cell Lung Cancermentioning

confidence: 99%

Alternative Energy: Breaking Down the Diverse Metabolic Features of Lung Cancers

2021

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Metabolic reprogramming is a hallmark of cancer initiation, progression, and relapse. From the initial observation that cancer cells preferentially ferment glucose to lactate, termed the Warburg effect, to emerging evidence indicating that metabolic heterogeneity and mitochondrial metabolism are also important for tumor growth, the complex mechanisms driving cancer metabolism remain vastly unknown. These unique shifts in metabolism must be further investigated in order to identify unique therapeutic targets for individuals afflicted by this aggressive disease. Although novel therapies have been developed to target metabolic vulnerabilities in a variety of cancer models, only limited efficacy has been achieved. In particular, lung cancer metabolism has remained relatively understudied and underutilized for the advancement of therapeutic strategies, however recent evidence suggests that lung cancers have unique metabolic preferences of their own. This review aims to provide an overview of essential metabolic mechanisms and potential therapeutic agents in order to increase evidence of targeted metabolic inhibition for the treatment of lung cancer, where novel therapeutics are desperately needed.

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Section: Small Cell Lung Cancermentioning

confidence: 99%

Alternative Energy: Breaking Down the Diverse Metabolic Features of Lung Cancers

2021

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“…SCLC characteristically exhibits loss of the tumor suppressor genes RB1 and TP53 [5][6][7][8][9]. Approximately 30% of SCLC tumors harbor amplification or overexpression of the transcription factor cMYC (MYC), which has been associated with more aggressive behavior and therapeutic resistance in some investigations [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Targeting MYC-enhanced glycolysis for the treatment of small cell lung cancer

et al. 2021

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Introduction The transcription factor MYC is overexpressed in 30% of small cell lung cancer (SCLC) tumors and is known to modulate the balance between two major pathways of metabolism: glycolysis and mitochondrial respiration. This duality of MYC underscores the importance of further investigation into its role in SCLC metabolism and could lead to insights into metabolic targeting approaches. Methods We investigated differences in metabolic pathways in transcriptional and metabolomics datasets based on cMYC expression in patient and cell line samples. Metabolic pathway utilization was evaluated by flow cytometry and Seahorse extracellular flux methodology. Glycolysis inhibition was evaluated in vitro and in vivo using PFK158, a small molecular inhibitor of PFKFB3. Results MYC-overexpressing SCLC patient samples and cell lines exhibited increased glycolysis gene expression directly mediated by MYC. Further, MYC-overexpressing cell lines displayed enhanced glycolysis consistent with the Warburg effect, while cell lines with low MYC expression appeared more reliant on oxidative metabolism. Inhibition of glycolysis with PFK158 preferentially attenuated glucose uptake, ATP production, and lactate in MYC-overexpressing cell lines. Treatment with PFK158 in xenografts delayed tumor growth and decreased glycolysis gene expression. Conclusions Our study highlights an in-depth characterization of SCLC metabolic programming and presents glycolysis as a targetable mechanism downstream of MYC that could offer therapeutic benefit in a subset of SCLC patients.

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Immune Checkpoint Blockade Outcome in Small-Cell Lung Cancer and Its Relationship With Retinoblastoma Mutation Status and Function

Dowlati

Abbas

Chan

et al. 2022

JCO Precision Oncology

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PURPOSE Immune checkpoint blockade (ICB) in conjunction with chemotherapy is approved for the treatment of extensive-stage small-cell lung cancer (SCLC). Although specific genomic abnormalities such as KEAP1 and STK11 gene mutations are associated with resistance to ICB in non-SCLC, no genomic abnormality has been found in association with resistance to ICB in SCLC. MATERIALS AND METHODS We first analyzed a retrospective cohort of 42 patients with SCLC treated with single-agent ICB or ICB combination (data set A). We then validated our results in a large prospective clinical trial of 460 patients (CheckMate 032, data set B). DNA and RNA sequencing were performed. RESULTS In data set A, patients treated with ICB with RB1 wild-type (WT) had a median overall survival (OS) of 23.1 months (95% CI, 9 to 37.5), whereas the RB1 mutant OS was 5 months (95% CI, 2.5 to 26; P = .04). Differentially expressed gene analysis between RB1 mutant and RB1 WT samples indicated the enrichment of downregulated immune-related genes and an immune exclusion phenotype among RB1 mutant but not in the RB1 WT tumor samples. We then assessed results from 460 patients enrolled in CheckMate 032, a trial of nivolumab (NIVO) or NIVO + ipilimumab only in SCLC. In this large cohort, RB1 WT patients had significantly improved outcome with NIVO therapy compared with mutant patients (hazard ratio, 1.41; 95% CI, 1.02 to 2.01; P = .041). High RB1 loss-of-function (LOF) signature scores significantly associated with neuroendocrine subtypes (ASCL1 and NeuroD1). However, neuroendocrine subtypes did not associate with OS. Remarkably, patients with lower RB1 LOF scores had longer OS following treatment with NIVO. CONCLUSION SCLC patients with RB1 WT status or lower RB1 LOF signature scores by transcriptomics have better outcomes with ICB monotherapy.

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Genomic alterations in small cell lung cancer and their clinical relevance

Cited by 3 publications

References 10 publications

Alternative Energy: Breaking Down the Diverse Metabolic Features of Lung Cancers

Alternative Energy: Breaking Down the Diverse Metabolic Features of Lung Cancers

Targeting MYC-enhanced glycolysis for the treatment of small cell lung cancer

Immune Checkpoint Blockade Outcome in Small-Cell Lung Cancer and Its Relationship With Retinoblastoma Mutation Status and Function

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