Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer

Rudin, Charles M.; Durinck, Steffen; Stawiski, Eric; Poirier, John T.; Modrušan, Zora; Shames, David S.; Bergbower, Emily Anne Smith; Guan, Yinghui; Shin, James; Guillory, Joseph; Rivers, Celina Sanchez; Foo, Catherine K.; Bhatt, Deepali; Stinson, Jeremy; Gnad, Florian; Haverty, Peter M.; Gentleman, Robert; Chaudhuri, Subhra; Janakiraman, Vasantharajan; Jaiswal, Bijay S.; Parikh, Chaitali; Yuan, Wenlin; Zhang, Zemin; Koeppen, Hartmut; Wu, Thomas D.; Stern, Howard M.; Yauch, Robert L.; Huffman, Kenneth E.; Paskulin, Diego D’Ávila; Illei, Peter B.; Varella‐Garcia, Marileila; Gazdar, Adi F.; Sauvage, Frédéric J. de; Bourgon, Richard; Minna, John D.; Brock, Malcolm V.; Seshagiri, Somasekar

doi:10.1038/ng.2405

Cited by 917 publications

(940 citation statements)

References 46 publications

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“…More recently, whole-genome sequencing of SCLC specimens have uncovered potential driver mutations such as PTEN mutation or FGFR1 amplification, both of which occur at relatively low frequency (28,30). In one previous study, SOX2 amplification was found in approximately 27% of SCLC samples, and SOX2 knockdown by shRNA inhibited proliferation of SCLC cells with SOX2 gene amplification (30).…”

Section: Discussionmentioning

confidence: 99%

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Sensitivity of Small Cell Lung Cancer to BET Inhibition Is Mediated by Regulation of ASCL1 Gene Expression

Lenhart

Kirov

Desilva

et al. 2015

Molecular Cancer Therapeutics

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The BET (bromodomain and extra-terminal) proteins bind acetylated histones and recruit protein complexes to promote transcription elongation. In hematologic cancers, BET proteins have been shown to regulate expression of MYC and other genes that are important to disease pathology. Pharmacologic inhibition of BET protein binding has been shown to inhibit tumor growth in MYC-dependent cancers, such as multiple myeloma. In this study, we demonstrate that small cell lung cancer (SCLC) cells are exquisitely sensitive to growth inhibition by the BET inhibitor JQ1. JQ1 treatment has no impact on MYC protein expression, but results in downregulation of the lineage-specific transcription factor ASCL1. SCLC cells that are sensitive to JQ1 are also sensitive to ASCL1 depletion by RNAi. Chromatin immunoprecipitation studies confirmed the binding of the BET protein BRD4 to the ASCL1 enhancer, and the ability of JQ1 to disrupt the interaction. The importance of ASCL1 as a potential driver oncogene in SCLC is further underscored by the observation that ASCL1 is overexpressed in >50% of SCLC specimens, an extent greater than that observed for other putative oncogenes (MYC, MYCN, and SOX2) previously implicated in SCLC. Our studies have provided a mechanistic basis for the sensitivity of SCLC to BET inhibition and a rationale for the clinical development of BET inhibitors in this disease with high unmet medical need.

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Section: Discussionmentioning

confidence: 99%

“…2B). SOX2, another transcription factor previously implicated in lung cancer (28), is also highly expressed in DMS53 cells, but was only modestly affected at the highest concentration of JQ1 tested (Fig. 2B).…”

Section: Jq1 Regulates Ascl1 Expression In Sclcmentioning

confidence: 98%

Sensitivity of Small Cell Lung Cancer to BET Inhibition Is Mediated by Regulation of ASCL1 Gene Expression

Lenhart

Kirov

Desilva

et al. 2015

Molecular Cancer Therapeutics

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“…13). Three landmark studies comprehensively characterized the SCLC genomic landscape, identifying alterations in genes encoding histone modifying proteins and transcription factors, including SOX2 and NOTCH family genes (10,14,15). These studies revealed a mutation rate of 5.5 to 8.6 coding mutations per Mb (10,14,15).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Potter

Galvin

Brown

et al. 2016

Molecular Cancer Therapeutics

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Most small cell lung cancer (SCLC) patients are initially responsive to cytotoxic chemotherapy, but almost all undergo fatal relapse with progressive disease, highlighting an urgent need for improved therapies and better patient outcomes in this disease. The proapoptotic BH3 mimetic ABT-737 that targets BCL-2 family proteins demonstrated good single-agent efficacy in preclinical SCLC models. However, so far clinical trials of the BH3 mimetic Navitoclax have been disappointing. We previously demonstrated that inhibition of a PI3K/BMX cell survival signaling pathway sensitized colorectal cancer cells to ABT-737. Here, we show that SCLC cell lines, which express high levels of BMX, become sensitized to ABT-737 upon inhibition of PI3K in vitro, and this is dependent on inhibition of the PI3K-BMX-AKT/mTOR signaling pathway. Consistent with these cell line data, when combined with Navitoclax, PI3K inhibition suppressed tumor growth in both an established SCLC xenograft model and in a newly established circulating tumor cell-derived explant (CDX) model generated from a blood sample obtained at presentation from a chemorefractory SCLC patient. These data show for the first time that a PI3K/BMX signaling pathway plays a role in SCLC cell survival and that a BH3 mimetic plus PI3K inhibition causes prolonged tumor regression in a chemorefractory SCLC patient-derived model in vivo. These data add to a body of evidence that this combination should move toward the clinic.

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“…85 Interestingly, SOX2 amplification was found in 27% of samples. SOX proteins are involved in stem cell renewal, as are the NOTCH and Hedgehog pathways, which were also frequently dysregulated.…”

Section: Issues In Specific Tumor Typesmentioning

confidence: 99%

NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

Venook¹,

Arcila²,

Benson³

et al. 2014

J Natl Compr Canc Netw

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Defining treatment susceptible or resistant populations of cancer patients through the use of genetically defined biomarkers has revolutionized cancer care in recent years for some disease/patient groups. Research continues to show that histologically defined diseases are diverse in their expression of unique mutations or other genetic alterations, however, which presents both opportunities for the development of personalized cancer treatments, but increased difficulty in testing these therapies because potential patient populations are divided into ever-smaller numbers. To address some of the growing challenges in biomarker development and clinical trial design, NCCN assembled a group of experts across specialties and solid tumor disease types to begin to define the problems and to consider alternate ways of designing clinical trials in the era of multiple biomarkers and targeted therapies. Results from that discussion are presented, focusing on issues of clinical trial design from the perspective of statisticians, clinical researchers, regulators, pathologists and information developers.

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Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer

Cited by 917 publications

References 46 publications

Sensitivity of Small Cell Lung Cancer to BET Inhibition Is Mediated by Regulation of ASCL1 Gene Expression

Sensitivity of Small Cell Lung Cancer to BET Inhibition Is Mediated by Regulation of ASCL1 Gene Expression

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

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