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M. Sanchez-cespedes

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    MS 26 - Genomic Alterations and Drug Targets in Small Cell Lung Cancer (ID 44)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MS26.02 - The MYC/MAX and the SWI/SNF Networks: Biological Understanding and Therapeutic Applications (ID 1964)

      14:15 - 15:45  |  Author(s): M. Sanchez-cespedes

      • Abstract
      • Presentation

      The SWI/SNF chromatin-remodeling complex modifies the structure of the chromatin by the ATP-dependent disruption of DNA–histone interactions at the nucleosomes to activate or repress gene expression. The widespread occurrence of alterations at genes encoding different components of the SWI/SNF complex reveals an important new feature that sustains cancer development and offers novel potential strategies for cancer therapeutics. We discovered that in lung cancer the SWI/SNF component, BRG1 (also called SMARCA4), is genetically inactivated in about thirty per cent of non-small cell lung cancers (NSCLC), and that its inactivation occurs in a background of wild type MYC (either C, L or N). Here, we also report our discovery of tumor-specific inactivation of the MYC-associated factor X gene, MAX, in about ten percent of small cell lung cancers (SCLC). This is mutually exclusive with alterations at MYC and BRG1. We also demonstrate that BRG1 regulates the expression of MAX through direct recruitment to the MAX promoter, and that depletion of BRG1 strongly hinders cell growth, specifically in MAX-deficient cells, heralding a synthetic lethal interaction. Furthermore, MAX requires BRG1 to activate neuroendocrine transcriptional programs and to up-regulate MYC-targets, such as glycolytic-related genes. Finally, we observed genetic inactivation of the MAX dimerization protein, MGA, in lung cancers with wild type components of the SWI/SNF or MYC pathways. Our results provide evidence that an aberrant SWI/SNF-MYC network is essential for lung cancer development. Altogether, the genetic observations coupled with the functional evidence demonstrate that an aberrant SWI/SNF-MYC network is essential for lung cancer development, and opens novel therapeutic possibilities for the treatment of SCLC patients with MAX-deficient tumors. In healthy adults and during embryonic development, the complex is involved in the control of cell differentiation and in the specification of different tissues. The effect of the SWI/SNF complex on some of these processes is, at least in part, related to its involvement in regulating hormone-responsive promoters. Components of the SWI/SNF complex bind to various nuclear receptors, such as those of estrogen, progesterone, androgen, glucocorticoids and retinoic acid, thereby adapting the gene expression programs to the demands of the cell environmental requirements. Retinoic acid (RA) and glucorticoids (GC) are well known modulators of cell differentiation, embryonic development and morphogenesis. Their role in promoting cell differentiation makes it possible to use GC and RA therapeutically to treat some types of cancers. GC are part of the curative treatment of acute lymphoblastic leukemia while RA is the therapeutic agent for some neuroblastomas and acute promyelocytic leukemia, which both carry the PML–RARa gene fusion. GC are also used as a co-medication in the therapy of solid tumors, because of their effectiveness in treating the malignancy, or due to their less severe side effects in cancer treatment, such as electrolyte imbalance, nausea and emesis. However, most solid tumors, including lung cancers, are refractory to GC- and RA-based therapies. Underlying some cases of refractoriness to GC and RA is a dysfunctional SWI/SNF complex, for example due to alterations at BRG1. On the other hand, compounds that modulate the structure of the chromatin are currently used to treat cancer. These include histone deacetylase (HDAC) inhibitors, in hematological malignancies and cutaneous T-cell lymphomas, and inhibitors of DNA methylation such as azacytidine for myelodysplasic syndrome. HDACs and DNA methylation inhibitors promote gene transcription by increasing DNA accessibility through the inhibition of histone deacetylation and DNA methylation, respectively. These drugs have been tested in lung cancer patients in two studies, in which they showed no major responses. However, in a phase I/II trial, the combination of the two inhibitors produced a median survival of the entire cohort that was significantly longer than those of the existing therapeutic options. Here, we aimed to determine whether there could be a therapeutic use for GC plus RA (GC/RA) in combination with the epigenetic drugs azacytidine and SAHA (A/S) for treating lung cancers carrying BRG1 inactivation or MYC amplification. We found that in vitro, GC/RA treatment reduced growth, triggered pro-differentiation gene expression signatures and downregulated MYC, in MYC-amplified but not in most BRG1-mutant lung cancer cells. The co-administration of A/S enhanced all these effects, accompanied by sustained reductions in genome-wide DNA methylation. In vivo, treatments with GC/RA improved overall survival of mice implanted with MYC-amplified cells and reduced tumor-cell viability and cell proliferation. Thus, we propose that the combination of retinoids, corticoids and epigenetic treatments of lung tumors with MYC amplification constitute a strategy for therapeutic intervention in this otherwise incurable disease. REFERENCES Collins SJ. The role of retinoids and retinoic acid receptors in normal hematopoiesis. Leukemia 2002; 16, 1896–905. Liu SV, Fabbri M, Gitlitz BJ, Laird-Offringa IA. Epigenetic therapy in lung cancer. Front Oncol 2013; 3, 135. Medina PP et al. Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell lines. Hum Mut 2008; 29, 617-22a. Pottier N et al. The SWI/SNF chromatin-remodeling complex and glucocorticoid resistance in acute lymphoblastic leukemia. J Natl Cancer Inst 2008; 100, 1792-803. Rodriguez-Nieto S et al. Massive parallel DNA pyrosequencing analysis of the tumor suppressor BRG1/SMARCA4 in lung primary tumors. Hum Mut 2011; 32, E1999-2017. Romero OA et al. The tumour suppressor and chromatin-remodelling factor BRG1 antagonizes Myc activity and promotes cell differentiation in human cancer. EMBO Mol Med 2012; 4, 603-16. Romero OA et al. MAX inactivation in small cell lung cancer disrupts MYC-SWI/SNF programs and is synthetic lethal with BRG1. Cancer Discov 2014; 4, 292-303. Romero OA, Sanchez-Cespedes M. The SWI/SNF genetic blockade: effects in cell differentiation, cancer and developmental diseases. Oncogene 2014; 33, 2681-9. Rutz HP. Effects of corticosteroid use on treatment of solid tumours. Lancet 2002; 360, 1969–70. Wilson GB,Roberts CWM. SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer 2011; 11, 481-92.

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