SMARCA4 supports the oncogenic landscape of KRAS -driven lung tumors

Cancer resequencing studies identify recurrent mutations in the switch/sucrose non-fermentable (SWI/SNF) complex at an unexpectedly high frequency across many cancer types. Some SWI/SNF mutations appear to be loss-of-function events, implying that the intact SWI/SNF complex is tumor suppressive. We examined the distribution and function of mutations, the most frequently mutated SWI/SNF complex gene in lung adenocarcinoma, using human cancers, cell lines and mouse model systems. We found that lung adenocarcinomas harboring activated oncogenes have fewer deleterious mutations in and express higher levels of the mRNA than cancers without activated oncogenes, indicating distinct dependencies on in these two settings. Surprisingly, intact promoted the growth and tumorgenicity of -driven mouse lung tumors and human cells. Mechanistically, we found that supports the oncogenic transcriptional/signaling landscape of -driven mouse lung cancer. This dependency on the chromatin maintenance machinery in established cancer cells support treatments directed towards pathogenic SWI/SNF complexes in lung adenocarcinoma and other malignancies.