RESEARCH SUMMARY

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

Cigall Kadoch, PhD

Study Summary: 
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.

Impact:
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.

Funding:
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.