Components of the SWI/SNF chromatin-remodeling complex, such as INI1, are inactivated in human cancer and, thus, act as tumor suppressors. Here we screened for mutations the entire coding sequence of BRG1 (SMARCA4), which encodes the ATPase of the complex, in 59 lung cancer cell lines of the most common histopathological types. Mutations were detected in 24% of the cancer cell lines, many of them in cells commonly used for lung cancer research. All mutations were homozygous and most predicted truncated proteins. The alterations were significantly more frequent in the non-small-cell lung cancer (NSCLC) type (13/37, 35%) as compared to the small-cell lung cancer (SCLC) type (1/19, 5%) (P<0.05; Fisher's Exact test) and BRG1 was the fourth most frequently altered gene in NSCLC cell lines. BRG1 mutations coexisted with mutations/deletions at KRAS, LKB1, NRAS, P16, and P53. However, alterations at BRG1 always occurred in the absence of MYC amplification, suggesting a common role in lung cancer development. In conclusion, our data strongly support that BRG1 is a bona fide tumor suppressor and a major factor in lung tumorigenesis.

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]