Neuroendocrine negative SCLC is mostly RB1 WT and may be sensitive to CDK4/6 inhibition

Sonkin, Dmitriy; Vural, Suleyman; Thomas, Anish; Teicher, Beverly A.

doi:10.1101/516351

Cited by 10 publications

(20 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These subtypes are the neuroendocrine subtypes SCLC-A ( ASCL1 -positive) and SCLC-N ( NEUROD1 -positive) and the non-neuroendocrine subtypes SCLC-P ( POU2F3 -positive) and SCLC-Y ( YAP1 -positive) [ 25 ]. Previous work has demonstrated activity of CDK4/6 inhibitors in RB1 wild-type SCLC cell lines [ 26 , 27 ]. Based on these results, a clinical trial is testing abemaciclib, a CDK4/6 inhibitor, as a single agent in ED-SCLC patients with wild-type RB1 , with platinum refractory disease ( Identifier NCT04010357).…”

Section: Clinical Management Of Sclcmentioning

confidence: 99%

Current Status and Future Perspectives of Liquid Biopsy in Small Cell Lung Cancer

et al. 2021

View full text Add to dashboard Cite

Approximately 19% of all cancer-related deaths are due to lung cancer, which is the leading cause of mortality worldwide. Small cell lung cancer (SCLC) affects approximately 15% of patients diagnosed with lung cancer. SCLC is characterized by aggressiveness; the majority of SCLC patients present with metastatic disease, and less than 5% of patients are alive at 5 years. The gold standard of SCLC treatment is platinum and etoposide-based chemotherapy; however, its effects are short. In recent years, treatment for SCLC has changed; new drugs have been approved, and new biomarkers are needed for treatment selection. Liquid biopsy is a non-invasive, rapid, repeated and alternative tool to the traditional tumor biopsy that could allow the most personalized medicine into the management of SCLC patients. Circulating tumor cells (CTCs) and cell-free DNA (cfDNA) are the most commonly used liquid biopsy biomarkers. Some studies have reported the prognostic factors of CTCs and cfDNA in SCLC patients, independent of the stage. In this review, we summarize the recent SCLC studies of CTCs, cfDNA and other liquid biopsy biomarkers, and we discuss the future utility of liquid biopsy in the clinical management of SCLC.

show abstract

Section: Clinical Management Of Sclcmentioning

confidence: 99%

Current Status and Future Perspectives of Liquid Biopsy in Small Cell Lung Cancer

et al. 2021

View full text Add to dashboard Cite

show abstract

“…We examined association of log(IC50) of these agents with methylation of individual probes and gene regions of 78 genes representing drug-specific targets and 48 additional genes involved in drug target pathways (Supplementary Table 2). In addition, we analyzed association of methylation of log(IC50) of each of the 44 agents with methylation of individual probes and gene regions of 159 proteincoding genes that included genes with relevance to SCLC lineage determination; SCLC lineage markers; genes that carry frequent mutations or genome alterations in SCLC; genes which are commonly inactivated, overexpressed, or epigenetically modified in SCLC tumors or in specific SCLC subtypes; as well as genes previously reported as being involved in pathways leading to SCLC pathogenesis; or those suggested as being relevant to SCLC response to chemotherapy [3,5,11,13,15,24,[34][35][36][37][38][39]. The list of these genes is provided in the legend to Supplementary Table 2.…”

Section: Association Of Methylation Of Candidate Genes With Selectedmentioning

confidence: 99%

“…The probes cg25627144 and cg18124721 in the TSS200 of the DLL3 (delta-like ligand 3) gene and the entire TSS200 region were associated with the Bcl-2 inhibitor ABT-737 (ρ = 0.5506 and 0.4850, p FDR = 0.0515 and 0.1366 for probes; ρ = 0.4762, p FDR = 0.1260 for TSS200; Table 3, Supplementary Tables 6, 7 and 8), and cg25627144 was also associated with another Bcl-2 inhibitor, ABT-263 (ρ = 0.4926, p FDR = 0.1282; Supplementary Table 7). DLL3, encoding a Notch pathway regulator and a promising clinical target in SCLC treatment, is upregulated in ASCL1-high SCLC tumors; in contrast, DLL3 expression is diminished in RB wild-type tumors and in SCLC tumors not expressing neuroendocrine markers [2,3,39]. Methylation of all DLL3 probes was significantly negatively associated with expression of the DLL3 transcript, NM_016941 (cluster ID 3833122; ρ = − 0.4426, p = 0.0002 for the strongest association).…”

Section: Association Of Methylation Of Probes and Regions In Candidatmentioning

confidence: 99%

Epigenome-wide DNA methylation analysis of small cell lung cancer cell lines suggests potential chemotherapy targets

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background: Small cell lung cancer (SCLC) is an aggressive neuroendocrine lung cancer. SCLC progression and treatment resistance involve epigenetic processes. However, links between SCLC DNA methylation and drug response remain unclear. We performed an epigenome-wide study of 66 human SCLC cell lines using the Illumina Infinium MethylationEPIC BeadChip array. Correlations of SCLC DNA methylation and gene expression with in vitro response to 526 antitumor agents were examined. Results: We found multiple significant correlations between DNA methylation and chemosensitivity. A potentially important association was observed for TREX1, which encodes the 3′ exonuclease I that serves as a STING antagonist in the regulation of a cytosolic DNA-sensing pathway. Increased methylation and low expression of TREX1 were associated with the sensitivity to Aurora kinase inhibitors AZD-1152, SCH-1473759, SNS-314, and TAK-901; the CDK inhibitor R-547; the Vertex ATR inhibitor Cpd 45; and the mitotic spindle disruptor vinorelbine. Compared with cell lines of other cancer types, TREX1 had low mRNA expression and increased upstream region methylation in SCLC, suggesting a possible relationship with SCLC sensitivity to Aurora kinase inhibitors. We also identified multiple additional correlations indicative of potential mechanisms of chemosensitivity. Methylation of the 3′UTR of CEP350 and MLPH, involved in centrosome machinery and microtubule tracking, respectively, was associated with response to Aurora kinase inhibitors and other agents. EPAS1 methylation was associated with response to Aurora kinase inhibitors, a PLK-1 inhibitor and a Bcl-2 inhibitor. KDM1A methylation was associated with PLK-1 inhibitors and a KSP inhibitor. Increased promoter methylation of SLFN11 was correlated with resistance to DNA damaging agents, as a result of low or no SLFN11 expression. The 5′ UTR of the epigenetic modifier EZH2 was associated with response to Aurora kinase inhibitors and a FGFR inhibitor. Methylation and expression of YAP1 were correlated with response to an mTOR inhibitor. Among nonneuroendocrine markers, EPHA2 was associated with response to Aurora kinase inhibitors and a PLK-1 inhibitor and CD151 with Bcl-2 inhibitors.

show abstract

“…These distinct gene expression profiles will guide us in designing new clinical trials. Recent advances in using patient-derived xenograft (PDX) models based on biopsy/resected tumors, CTCs, genetically engineered mouse models (GEMM), as well as omics profiling will drastically enhance our capacity to identify and test novel drugs and discover biomarkers for treatment and prognostication [93,149].…”

Section: Future Directionsmentioning

confidence: 99%

Small Cell Lung Cancer from Traditional to Innovative Therapeutics: Building a Comprehensive Network to Optimize Clinical and Translational Research

Subbiah

Nam

Garg

et al. 2020

JCM

View full text Add to dashboard Cite

Small cell lung cancer (SCLC) is an aggressive, complex disease with a distinct biology that contributes to its poor prognosis. Management of SCLC is still widely limited to chemotherapy and radiation therapy, and research recruitment still poses a considerable challenge. Here, we review the current standard of care for SCLC and advances made in utilizing immunotherapy. We also highlight research in the development of targeted therapies and emphasize the importance of a team-based approach to make clinical advances. Building an integrative network between an academic site and community practice sites optimizes biomarker and drug target discovery for managing and treating a difficult disease like SCLC.

show abstract

Neuroendocrine negative SCLC is mostly RB1 WT and may be sensitive to CDK4/6 inhibition

Cited by 10 publications

References 35 publications

Current Status and Future Perspectives of Liquid Biopsy in Small Cell Lung Cancer

Current Status and Future Perspectives of Liquid Biopsy in Small Cell Lung Cancer

Epigenome-wide DNA methylation analysis of small cell lung cancer cell lines suggests potential chemotherapy targets

Small Cell Lung Cancer from Traditional to Innovative Therapeutics: Building a Comprehensive Network to Optimize Clinical and Translational Research

Contact Info

Product

Resources

About