PTEN Is a Potent Suppressor of Small Cell Lung Cancer

Cui, Min; Augert, Arnaud; Rongione, Michael; Conkrite, Karina L.; Parazzoli, Susan; Nikitin, Alexander Yu.; Ingolia, Nicholas T.; MacPherson, David

doi:10.1158/1541-7786.mcr-13-0554

Cited by 108 publications

(105 citation statements)

References 19 publications

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“…Other druggable targets of ASCL1 were identified by our ChIP-Seq analysis, representing additional potential therapeutic interventions (SI Appendix, Table S7). A mouse model exists for LCNE carcinomas, which may enhance the potential for testing therapeutic agents in vivo (31).…”

Section: Discussionmentioning

confidence: 99%

ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancers

Augustyn¹,

Borromeo

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

218

241

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Aggressive neuroendocrine lung cancers, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), represent an understudied tumor subset that accounts for approximately 40,000 new lung cancer cases per year in the United States. No targeted therapy exists for these tumors. We determined that achaetescute homolog 1 (ASCL1), a transcription factor required for proper development of pulmonary neuroendocrine cells, is essential for the survival of a majority of lung cancers (both SCLC and NSCLC) with neuroendocrine features. By combining whole-genome microarray expression analysis performed on lung cancer cell lines with ChIPSeq data designed to identify conserved transcriptional targets of ASCL1, we discovered an ASCL1 target 72-gene expression signature that (i) identifies neuroendocrine differentiation in NSCLC cell lines, (ii) is predictive of poor prognosis in resected NSCLC specimens from three datasets, and (iii) represents novel "druggable" targets. Among these druggable targets is B-cell CLL/lymphoma 2, which when pharmacologically inhibited stops ASCL1-dependent tumor growth in vitro and in vivo and represents a proof-of-principle ASCL1 downstream target gene. Analysis of downstream targets of ASCL1 represents an important advance in the development of targeted therapy for the neuroendocrine class of lung cancers, providing a significant step forward in the understanding and therapeutic targeting of the molecular vulnerabilities of neuroendocrine lung cancer.ASCL1 transcriptome | target discovery | personalized therapy G ene expression signatures from large cohorts of lung tumors suggest that cancers with neuroendocrine features appear in ∼10% of pathologically diagnosed non-small cell lung cancers (NSCLCs) (1, 2), whereas small cell lung cancers (SCLCs) compose 15-20% of all lung cancer cases (3). In the United States, this represents nearly 40,000 patients per year presenting with a high-grade neuroendocrine lung tumor. Molecular and functional characterization of these aggressive tumors, along with the development of relevant preclinical models, is needed to rationally develop and test new targeted therapies.A highly expressed gene in the class of neuroendocrine lung cancers is the lineage-specific transcription factor achaete-scute homolog 1 (ASCL1) (4, 5). ASCL1 is required to establish the lineage of pulmonary neuroendocrine cells (6) and is necessary for the continued survival of SCLCs (7, 8). ASCL1's appearance in an NSCLC subset, neuroendocrine NSCLC (NE-NSCLC), is a recent and unexplained finding (9), and, importantly, its role as a potential lineage oncogene in lung tumors has been heretofore unexplored. The lineage addiction hypothesis in cancer suggests that certain tumors arise from dysregulation of genes involved in normal development. Hijacking these genes, which are involved in numerous facets of growth, cell division, and differentiation, provides a budding precancerous cell with the framework within which to progress to full tumorigenicity. The transcription factors...

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Section: Discussionmentioning

confidence: 99%

ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancers

Augustyn¹,

Borromeo

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

218

241

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“…In this mouse model, Rb lox/lox ;p53 lox/lox ;Pten lox/lox mice were infected intratracheally with Ad-Cre driven by a neuroendocrine (Calcitonin/CGRP) promoter (Ad-CGRP-Cre) (as in Sutherland et al 2011;McFadden et al 2014). The Ad-CGRP-Cre approach was taken because combined deletion of Rb/p53/Pten throughout the lung using the more widely active Ad-CMV-Cre leads to substantial adenocarcinoma that impairs study of SCLC (Cui et al 2014). When mice were examined 4 mo following Ad-CGRP-Cre delivery, we found clear reductions in number and size of early tumors in the Mycl-deleted model (Fig.…”

Section: Mycl Inactivation Suppresses Sclcmentioning

confidence: 99%

“…The SCLC mouse models bearing deletions in p53, Rb, p130, or Pten were previously described (Meuwissen et al 2003;Schaffer et al 2010;Cui et al 2014). Construction of the Mycl lox strain and Chga-GFP transgenic strain expressing GFP under control of the Chga promoter is described in the Supplemental Material.…”

Section: Mouse Strains Ad-cre Infection and Subcutaneous Allograftsmentioning

confidence: 99%

Genetic requirement forMycland efficacy of RNA Pol I inhibition in mouse models of small cell lung cancer

Kim

et al. 2016

Genes Dev.

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Small cell lung cancer (SCLC) is a devastating neuroendocrine carcinoma. MYCL (L-Myc) is frequently amplified in human SCLC, but its roles in SCLC progression are poorly understood. We isolated preneoplastic neuroendocrine cells from a mouse model of SCLC and found that ectopic expression of L-Myc, c-Myc, or N-Myc conferred tumorforming capacity. We focused on L-Myc, which promoted pre-rRNA synthesis and transcriptional programs associated with ribosomal biogenesis. Deletion of Mycl in two genetically engineered models of SCLC resulted in strong suppression of SCLC. The high degree of suppression suggested that L-Myc may constitute a therapeutic target for a broad subset of SCLC. We then used an RNA polymerase I inhibitor to target rRNA synthesis in an autochthonous Rb/p53-deleted mouse SCLC model and found significant tumor inhibition. These data reveal that activation of RNA polymerase I by L-Myc and other MYC family proteins provides an axis of vulnerability for this recalcitrant cancer.

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“…Beyond loss of RB and p53, which is required for SCLC development, a number of other genes and signaling pathways are altered in SCLC tumors (12) and the roles of these genes/pathways can be tested in GEMMs. Ectopic expression of oncogenes such as Myc, Nfib or oncogenic forms of the Hedgehog pathway receptor Smo (14-17), or deletion of tumor suppressors such as the Rb family members p130 or Pten (18)(19)(20) in the Rb/p53 double knockout (DKO) model has led to new models with faster tumor development. With recent advances in genome engineering, including CRISPR/Cas9, it is likely that additional models will be soon available to the community.…”

Section: Autochthonous Gemms Of Sclcmentioning

confidence: 99%

“…This is possibly due to the still limited number of samples that have been analyzed in depth. Moreover, with the exception of Notch signaling (12), two Myc family members (c-Myc and L-Myc) (14), and Pten (18,20), very few of these recurrent alterations have been functionally tested in GEMMs or even PDX models. Thus, it is difficult to know if these genetic alterations represent distinct subtypes of SCLC that may have different growth properties or may respond to various therapies differently.…”

Section: Genomic Studies Of Human Sclc and Genetic Diversitymentioning

confidence: 99%

Tumor heterogeneity in small cell lung cancer defined and investigated in pre-clinical mouse models

Shue¹,

Lim²,

Sage³

2018

Transl. Lung Cancer Res.

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Small cell lung carcinoma (SCLC) is a neuroendocrine subtype of lung cancer characterized by its fast growth and aggressive nature. SCLC development is strongly associated with heavy cigarette smoking. In a majority of cases, SCLC tumors have already metastasized to distant sites at the time of first diagnosis. Except in rare cases when tumors are diagnosed early, treatment options are limited and usually consist of several rounds of chemotherapy with cisplatin/ carboplatin and etoposide. While this chemotherapy regimen often results in significant response and tumor shrinkage, relapse is usually quite rapid. A number of excellent reviews have recently discussed the key clinical features of SCLC and the current lack of efficient treatment despite a large number of clinical trials in the past three decades (1-4). New therapeutic approaches, including immunotherapies, are promising but at the time this review is written, there are still no approved targeted therapies for SCLC [reviewed in (5-8)].Here we discuss emerging data in the field on the role of tumor heterogeneity in the growth of SCLC and the response of these tumors to therapy, and how mouse models have been used to identify such tumor heterogeneity and investigate its role. We use the term "intertumoral" heterogeneity to describe how SCLC tumors in patients or mice evolve differently at the genetic and epigenetic level during tumor progression and metastasis. We use the term "intratumoral" heterogeneity to describe the different subpopulations of cells within tumors at any given time; in Abstract: Small cell lung carcinoma (SCLC) is a fast-growing, highly metastatic form of lung cancer. A major difference between SCLC and other forms of lung cancer is that SCLC tumors often respond well to chemotherapy initially; unfortunately, resistant tumors rapidly recur. In addition, despite a large number of clinical trials with a variety of therapeutic agents, little progress has been achieved in the past three decades in improving the survival of SCLC patients. These clinical observations indicate that SCLC tumors have a high degree of plasticity and rapid adaptability to changes in growth conditions. Here we consider recent evidence pointing to several levels of heterogeneity in SCLC that may explain the ability of these tumors to adjust to different microenvironment and therapeutics. In particular, we review new data pointing to the existence of several subpopulations of tumor cells that interact with each other to promote tumor growth.We also discuss how SCLC tumors that look similar at the histopathological level may actually represent distinct subtypes of tumors and how these differences impact the response to specific therapeutic agents.A better understanding of genetic and cellular heterogeneity will guide the development of personalized approaches to help SCLC patients.

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PTEN Is a Potent Suppressor of Small Cell Lung Cancer

Cited by 108 publications

References 19 publications

ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancers

ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancers

Genetic requirement forMycland efficacy of RNA Pol I inhibition in mouse models of small cell lung cancer

Tumor heterogeneity in small cell lung cancer defined and investigated in pre-clinical mouse models

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