The MEK5–ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer

Cristea, Sandra; Coles, Garry L.; Hornburg, Daniel; Gershkovitz, Maya; Arand, Julia; Cao, Siqi; Sen, Triparna; Williamson, Stuart C.; Kim, Jun W.; Drainas, Alexandros P.; He, Andrew; Cam, Laurent Le; Byers, Lauren A.; Snyder, M; Contrepois, Kévin; Sage, Julien

doi:10.1158/0008-5472.can-19-1027

Cited by 59 publications

(56 citation statements)

References 57 publications

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“…Again, Devarakonda S. et al had a similar finding in their ctDNA profiling, indicating the importance of RTK/RAS/RAF pathway in SCLC 13 . This is consistent with previous literature showing the essential role of the RTK/RAS/MAPK signaling in tumor growth, metastasis, and metabolism of SCLC 28 . Amplifications of FGFR1, HER2, and MET of this pathway as detected in our study may suggest therapeutic opportunities, given the emerging investigational agents or approved drugs targeting these aberrations either in SCLC or in other solid tumors 29 , 30 .…”

Section: Discussionsupporting

confidence: 93%

Genomic Profiling of Circulating Tumor DNA from Patients with Extensive-Stage Small Cell Lung Cancer Identifies Potentially Actionable Alterations

Yang

Wang²,

Lü

et al. 2021

J. Cancer

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Comprehensive genomic profiling may help uncover potentially actionable alterations in small cell lung cancer (SCLC) patients who have progressed on standard chemotherapy. However, tissue procurement may be extremely challenging for extensive-stage patients. We aimed to investigate the possibility of genomic profiling and detecting actionable alterations from blood in Chinese SCLC patients. Blood samples collected from extensive-stage SCLC pateints were subjected to circulating tumor DNA (ctDNA) extraction and targeted-next generation sequencing (NGS) using a 150-gene panel. A total of 1,300 aberrations were detected in 128 genes and 89.2% (116/130) patients harbored at least one oncogenic alteration. The most frequently mutated genes included TP53 (82.3%), RB1 (56.2%), LRP1B (40.8%) etc. and 54.6% of the patients had concurrent TP53/RB1 mutations. The RTK/RAS/RAF axis was the most frequently mutated oncogenic pathway. Samples harboring alterations in the DNA damaging repair (DDR), Notch, PI3K/mTOR, RTK/RAS/RAF, and Wnt pathways exhibited significantly higher blood tumor mutational burden (bTMB) than their wildtype counterparts. Classification based on OncoKB criteria detected potentially actionable alterations in about 50% of the population, half of which were bTMB-H and bMSI-H, indicating response to immune checkpoint inhibitors. Alterations in the RTK/RAS/RAF, DDR, and PI3K/mTOR also suggested potential sensitivity to matched targeted therapies or emerging investigational agents. Blood-based panel NGS is promising for delineating genomic landscape of SCLC and may also shed some light on treatment selection for Chinese SCLC patients.

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Section: Discussionsupporting

confidence: 93%

Genomic Profiling of Circulating Tumor DNA from Patients with Extensive-Stage Small Cell Lung Cancer Identifies Potentially Actionable Alterations

Yang

Wang²,

Lü

et al. 2021

J. Cancer

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“…Interestingly, the mevalonate and lipid synthesis pathway was recently shown to be controlled by MEK5/ERK5 and required for optimal growth in SCLC 77 . Of note, the mevalonate pathway is equally responsible for the synthesis of coenzyme Q10 (CoQ10), the reduced form of which (ubiquinol) is generated by FSP1 and was recently shown to act as a radical trapping agent preventing ferroptosis 55 , 56 .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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Loss of TP53 and RB1 in treatment-naïve small cell lung cancer (SCLC) suggests selective pressure to inactivate cell death pathways prior to therapy. Yet, which of these pathways remain available in treatment-naïve SCLC is unknown. Here, through systemic analysis of cell death pathway availability in treatment-naïve SCLC, we identify non-neuroendocrine (NE) SCLC to be vulnerable to ferroptosis through subtype-specific lipidome remodeling. While NE SCLC is ferroptosis resistant, it acquires selective addiction to the TRX anti-oxidant pathway. In experimental settings of non-NE/NE intratumoral heterogeneity, non-NE or NE populations are selectively depleted by ferroptosis or TRX pathway inhibition, respectively. Preventing subtype plasticity observed under single pathway targeting, combined treatment kills established non-NE and NE tumors in xenografts, genetically engineered mouse models of SCLC and patient-derived cells, and identifies a patient subset with drastically improved overall survival. These findings reveal cell death pathway mining as a means to identify rational combination therapies for SCLC.

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“…Other targets of recently emerging interest include selective metabolomic dependencies of SCLC. MEK5 and ERK5 have been recently identified as critical regulators of lipid metabolism of SCLC cells, suggesting these kinases as possible therapeutic targets (55). MYC-driven SCLC cells have been reported to be highly dependent on arginine-regulated pathways including polyamine biosynthesis and mTOR pathway activation; selective arginine depletion appeared to be highly effective in MYC-driven SCLC preclinical models (56).…”

Section: Other Emerging Targets In Sclcmentioning

confidence: 99%

Targeted Therapies and Biomarkers in Small Cell Lung Cancer

2020

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Small cell lung cancer (SCLC) is an aggressive malignancy characterized by rapid growth, early metastasis, and acquired therapeutic resistance. A majority of patients with SCLC have extensive-stage (ES) disease, defined as the presence of metastatic disease outside the hemithorax at first diagnosis. SCLC has been considered "a graveyard for drug development," with chemotherapy remaining the standard treatment for first-and second-line management until quite recently. In contrast to NSCLC, identifying therapeutic targets in SCLC has been challenging, partly because driver mutations are primarily loss of function, involving the tumor suppressor genes RB1 and TP53 or currently untargetable (e.g., amplification of MYC family members). Recent gene expression profiling of SCLC cells lines, patient samples and representative murine models, have led to a proposed delineation of four major subtypes for SCLC distinguished by differential expression of four key transcriptional regulators (ASCL1, NEUROD1, POU2F3, and YAP1). Our understanding of the biology of SCLC has indeed significantly improved recently due to the continued efforts of the dedicated investigators in this field, but the therapeutic options remain dismal. While recent results from immunotherapy trials are encouraging, most patients demonstrate either primary or rapid acquired resistance to current regimens, highlighting the clear need to improve the effectiveness and expand the scope of current therapeutic strategies. In this opinion article, we will discuss recent developments in the treatment of SCLC, focused on current understanding of the signaling pathways, the role of immunotherapy and targeted therapy, and emerging biomarkers of response to therapy in SCLC.

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The MEK5–ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer

Cited by 59 publications

References 57 publications

Genomic Profiling of Circulating Tumor DNA from Patients with Extensive-Stage Small Cell Lung Cancer Identifies Potentially Actionable Alterations

Genomic Profiling of Circulating Tumor DNA from Patients with Extensive-Stage Small Cell Lung Cancer Identifies Potentially Actionable Alterations

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

Targeted Therapies and Biomarkers in Small Cell Lung Cancer

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