The scientists concluded that chromatin availability modifications for key gene regulative programs underlie the difference between tki-resistant and adult EGFR-mutant cancer cell lines, and that epigenetic factors are most likely to be playing a key role in resistance. These EGFR-mutant patient-derived cancer cells are resistant to osimertinib when injected into mice.Fernando de MiguelDuring these experiments, the scientists became particularly interested in the SMARCA4 protein, a key part of the chromatin remodeling complex mSWI/SNF. Using epigenome analysis, the scientists discovered that mSWI/SNF complexes were located at different websites across the genome in TKI-resistant lung cancer cell lines versus drug-sensitive cell lines. The existence or absence of mSWI/SNF modified chromatin accessibility and altered particular transcriptional programs.To see if the cells could become re-sensitized to osimertinib, Politi, Kadoch, and their teams utilized brief barrette RNA to knock down SMARCA4 in the resistant cell lines.”We believe that the shift in chromatin accessibility that SMARCA4 and mSWI/SNF moderates in the resistant setting enables the cells to survive better, to multiply and divide much better, and also stand up to the stresses that are enforced by drugs, by triggering an antioxidant action in the cells,” said Politi.
Utilizing epigenome analysis, the scientists discovered that mSWI/SNF complexes were located at different websites across the genome in TKI-resistant lung cancer cell lines versus drug-sensitive cell lines. The existence or lack of mSWI/SNF transformed chromatin availability and altered specific transcriptional programs.To see if the cells might become re-sensitized to osimertinib, Politi, Kadoch, and their teams used short barrette RNA to knock down SMARCA4 in the resistant cell lines.”We believe that the shift in chromatin accessibility that SMARCA4 and mSWI/SNF moderates in the resistant setting allows the cells to survive much better, to multiply and divide better, and likewise hold up against the stresses that are enforced by drugs, by activating an antioxidant reaction in the cells,” said Politi.
