Author of

• 24750

  +

  MS01 - Cancer Pathways, Targeted Therapy and Resistance (ID 780)

  • Event: WCLC 2018
  • Type: Mini Symposium
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/24/2018, 10:30 - 12:00, Room 206 F

  • 24751

    +

    MS01.01 - Defects of the SWI/SNF OR MYC/MAX Pathways: Effects in Cell Differentiation and Therapeutic Opportunities (ID 11401)

    10:30 - 10:50  |  Presenting Author(s): Montse Sanchez-Cespedes
    • Abstract
    • Presentation
    • Slides

    Abstract
    

    The SWI/SNF complexes are ATP-dependent remodelers of the chromatin structure, by disrupting of DNA–histone interactions to activate or repress gene expression (Wilson et al. 2011). In healthy adults and during embryonic development, the complex is involved in the control of cell differentiation and in the specification of different tissues. 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. 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 (reviewed Romero et al. 2014).

    A few years ago, we discovered that, in lung cancer, the SWI/SNF component, SMARCA4 (also called BRG1), 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 (Medina et al. 2008). Nowadays, it is well established that other components of the complex are also commonly inactivated in most cancer types, including lung cancer (reviewed in Romero et al. 2014). Gene alterations of the SWI/SNF complex are significantly more common in NSCLC, as compared to small cell lung cancers (SCLC), and tend to associated with smoking habit. In addition, we reported the presence of tumor-specific inactivation of the MYC-associated factor X gene, MAX, in about ten percent of SCLC (Romero et al. 2014). The two events are mutually exclusive among them and with alterations at the MYC-family of genes. We also demonstrated that SMARCA4 regulates the expression of MAX and that depletion of SMARCA4 specifically in MAX-deficient cells strongly decreased cell growth, heralding a synthetic lethal interaction with potential therapeutic implications. Furthermore, MAX required of SMARCA4 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.

    The widespread occurrence of alterations at genes encoding different components of the SWI/SNF complex reveals an important new feature that sustains cancer development. Retinoic acid (RA) and glucorticoids (GC) are well known modulators of cell differentiation, embryonic development and morphogenesis. GCs and RA are part of the curative treatment of some malignancies, mostly leukemias (Collins et al. 2002; Rutz et al. 2002; Pottier et al. 2008). 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 SMARCA4 (Romero et al. 2002). 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 (Liu et al. 2013). HDACs and DNA methylation inhibitors promote gene transcription by increasing DNA accessibility through the inhibition of histone deacetylation and DNA methylation, respectively. In a preliminary study, these drugs, in combination, have shown promising results in the treatment of lung cancer patients. In lung cancer cell lines, we observed that GC plus RA (GC/RA) in combination with the epigenetic drugs azacytidine and SAHA (A/S) reduced growth, triggered pro-differentiation gene expression signatures and downregulated MYC, in MYC-amplified but not in most SMARCA4-mutant cells (Romero et al. 2017). In vivo, treatments with GC/RA improved overall survival of mice implanted with MYC-amplified cells and reduced tumor-cell viability and cell proliferation. We also found some effect of the SAHA treatment, alone in reducing the cell growth of MYC-amplified lung cancer cells but not those that are SMARCA4-deficient. 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.

    Altogether, the genetic observations coupled with the functional evidence demonstrate that an aberrant SWI/SNF-MYC network is essential for lung cancer development and open novel therapeutic possibilities for the treatment of lung cancer patients.

    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.

    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.

    Romero OA et al. Sensitization of retinoids and corticoids to epigenetic drugs in MYC-activated lung cancers by antitumor reprogramming. Oncogene 2017; 36, 1287-96.

    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.

    e353dbe42c8654f33588d4da0b517469

    Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

    Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.