SMARCA4 supports the oncogenic landscape of KRAS-driven lung tumors
John E. Greer,
Diana C Hargreaves,
Posted 20 Apr 2020
bioRxiv DOI: 10.1101/2020.04.18.043927
Posted 20 Apr 2020
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 SMARCA4 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 SMARCA4 and express higher levels of the mRNA than cancers without activated oncogenes, indicating distinct dependencies on SMARCA4 in these two settings. Surprisingly, intact Smarca4 promoted the growth and tumorgenicity of KrasG12D-driven mouse lung tumors and human cells. Mechanistically, we found that Smarca4 supports the oncogenic transcriptional/signaling landscape of KrasG12D-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. ### Competing Interest Statement The authors have declared no competing interest.
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