Study Uncovers Epigenetic Source of Resistance to Targeted Therapy in EGFR-mutant Lung Cancer
Study Title: Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer
Publication: Cancer Cell
Dana-Farber Cancer Institute Senior and Lead Authors: Cigall Kadoch, PhD; Claudia Gentile, PhD; Akshay Sankar
When lung cancers driven by mutations in the EGFR gene become resistant to osimertinib or other targeted therapies, epigenetic changes, rather than genetic changes, are often to blame. In a new study in Cancer Cell, researchers at the Dana-Farber Cancer Institute and Yale Cancer Center show that the main source of these changes are mSWI/SNF chromatin remodeling complexes, which alter gene activity by changing DNA architecture. In a series of experiments in cellular systems and animal models, the researchers found that blocking mSWI/SNF complexes – either chemically or genetically – reversed resistance to osimertinib in a subset of EGFR-mutant lung tumors. The findings suggest that mSWI/SNF-disrupting drugs, particularly SMARCA4/2 ATPase inhibitors, may offer a way to restore the potency of osimertinib in these tumors.
In certain EGFR-mutant lung tumors that are resistant to osimertinib, treatment with mSWI/SNF inhibitors, now in the clinic in Phase I trials, may reinstate Osimertinib sensitivity.
The research was supported by the National Institutes of Health; a Yale Cancer Center pilot grant; the Helen Gurley Brown Presidential Initiative at Dana-Farber; a Fundacion Ramon Areces Life and Matter Sciences Postdoctoral Fellowship; and the Howard Hughes Medical Institute.