Abstract IA02: Dissection of the BRG1 and MYC/MAX biological connection and its use in lung cancer therapeutics
Authors: Sanchez-Cespedes Montse 
Published: October 2015

Lung cancer is the first cause of death due to cancer in most western countries, in part because of the low efficacy of most current therapies. In this regard, understanding the genetic architecture of lung malignancies has proven to constitute a reliable strategy to develop novel anticancer agents and foretell response to therapies. Previously, we reported that one third of the lung tumors of the non-small cell lung cancer type (NSCLC) endure inactivation of BRG1, which constitutes the fourth most commonly altered gene in this type of cancer. Interestingly, we also observed that BRG1 inactivation and MYC amplification are mutually exclusive events in lung cancer, supporting previous observations of a functional relationship between the MYC and BRG1 proteins. The BRG1 gene codes for a member of the SWI/SNF chromatin remodeling complex, and its role in cancer development is still poorly understood, which hinders its potential use in clinical settings.

Here, I report our discovery on how the expression of wild type BRG1 in lung cancer cells up-regulates lung-specific transcripts, significantly restoring the gene expression signature of normal lung. Using cell lines from several cancer types we found that those lacking BRG1 do not respond to retinoic acid (RA) or glucocorticoids (GC), while restoration of BRG1 restitutes sensitivity, as determined by changes in cell morphology and gene expression. Conversely, in SH-SY5Y cells, a paradigm of RA-dependent differentiation, abrogation of BRG1 prevented the response to RA. We also demonstrated an antagonistic functional connection between BRG1 and MYC, whereby refractoriness to RA and GC by BRG1 inactivation involves deregulation of MYC activity. Mechanistically, these effects are mediated by BRG1 binding to MYC and MYC-target promoters to regulate their expression. Finally, BRG1 restoration significantly dampened invasion and progression, decreased MYC and restored responsiveness to RA in lung cancer cells orthotopically implanted in nude mice. This supports that BRG1 inactivation enables the cancer cell to sustain undifferentiated gene expression programs and prevent its response to environmental stimuli.

On the other hand, small cell lung cancer (SCLC) accounts for one-fifth of lung cancer diagnoses and is a highly aggressive malignancy. However, our knowledge of small cell lung cancer (SCLC) genetics is still very limited, amplification of L-MYC, N-MYC and C-MYC being some of the well-established gene alterations. In this presentation I will also report our discovery of biallelic and tumor-specific inactivation of the MYC-associated factor X gene, MAX, in SCLC. Alterations in MAX were mutually exclusive with alterations at MYC and BRG1, the latter coding for an ATPase of the SWI/SNF complex. Taking advantage of three lung cancer cell lines lacking MAX we studied the effects of restoring MAX activity and depleting BRG1 in these cells. The current work demonstrates 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. This heralds a synthetic lethal interaction between MAX and BRG1, and raise the possibility of developing a therapeutic strategy for patients with MAX-deficient tumors. Furthermore, it was observed that MAX requires BRG1 to activate neuroendocrine transcriptional programs and to up-regulate MYC-targets, such as glycolytic-related genes (e.g., LDHA, HK2, PDK1, PKM2, and PGK1). Finally, we also report genetic inactivation of the MAX dimerization protein, MGA, in lung cancers with wild type components of the SWI/SNF or MYC pathways.

Taken together, these observations 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.

Citation Format: Montse Sanchez-Cespedes. Dissection of the BRG1 and MYC/MAX biological connection and its use in lung cancer therapeutics. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr IA02.