MAX Inactivation in Small Cell Lung Cancer Disrupts MYC–SWI/SNF Programs and Is Synthetic Lethal with BRG1

Abstract

Our knowledge of small cell lung cancer (SCLC) genetics is still very limited, amplifi cation of L-MYC , N-MYC , and C-MYC being some of the well-established gene alterations. Here, we report our discovery of tumor-specifi c inactivation of the MYC-associated factor X gene, MAX , in SCLC. MAX inactivation is mutually exclusive with alterations of MYC and BRG1 , the latter coding for an ATPase of the switch/sucrose nonfermentable (SWI/SNF) complex. We demonstrate that BRG1 regulates the expression of MAX through direct recruitment to the MAX promoter, and that depletion of BRG1 strongly hinders cell growth, specifi cally in MAX-defi cient cells, heralding a synthetic lethal interaction. Furthermore, MAX requires BRG1 to activate neuroendocrine transcriptional programs and to upregulate MYC targets, such as glycolysis-related genes. Finally, inactivation of the MAX dimerization protein, MGA, was also observed in both non-small cell lung cancer and SCLC. Our results provide evidence that an aberrant SWI/SNF-MYC network is essential for lung cancer development. SIGNIFICANCE:We discovered that the MYC-associated factor X gene, MAX , is inactivated in SCLCs. Furthermore, we revealed a preferential toxicity of the inactivation of the chromatin remodeler BRG1 in MAX-defi cient lung cancer cells, which opens novel therapeutic possibilities for the treatment of patients with SCLC with MAX-defi cient tumors. Cancer Discov; 4(3);[292][293][294][295][296][297][298][299][300][301][302][303]

Sensitization of retinoids and corticoids to epigenetic drugs in MYC-activated lung cancers by antitumor reprogramming

“…Depletion of BRG1 in AmpMYC/wtBRG1 cells impairs responses to treatments with GC/RA and the combination with azacytidine and SAHA Next we depleted BRG1 in AmpMYC/wtBRG1 cells using two different shBRG1 (shBRG1#1 and shBRG1#4), previously validated by our group [5][6] (Figure 2a; Supplementary Figure S3a). In accordance with our previous results, 5 the depletion of BRG1 markedly reduced the ability of the cells to undergo changes in morphology following treatment with GC/RA and GC/RA combined with A/S (Figure 2b; Supplementary Figure S3b).…”

“…The cell lines were authenticated by genotyping for TP53 and other known mutations. 6 Genomic DNA and total RNA were extracted by standard protocols. The study was approved by the relevant institutional review boards and ethics committees.…”

“…The lentiviruses were generated within the 293T packaging cells, as previously described. 6 Cell viability assays (3-(4,5)-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)…”

“…[3][4][5] More recently, we noted tumor-specific inactivation of the MYC-associated factor X gene, MAX, in about 10% of small cell lung cancers, where it is present in tumors that are wild type for MYC and BRG1. 6 Altogether, the genetic observations coupled with functional studies [5][6][7][8] indicate the existence of an important network, involving SWI/SNF and MAX/ MYC that is critical to lung cancer development.…”

Targeting p300 Addiction inCBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation ofMYCExpression

“…62 ), or by establishing cells stably harboring plasmids expressing cDNAs (MYC: pLOC-MYC; CCND1: pLOC-CCND1; CDC45: pLOC-CCND1; Thermo Scientifi c). In one transient transfection method, cells were seeded in 12-well plates and transfected the next day with 1 μg of plasmid DNA using Lipofectamine 3000 (Invitrogen).…”