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News — Targeted therapies have revolutionized cancer treatment and the field of oncology. The FDA has approved over 70 targeted therapies for various cancer types, including lung cancer. Epidermal growth factor receptor (EGFR) mutations are found in a significant proportion of lung adenocarcinomas, and the use of tyrosine kinase inhibitors (TKIs) such as osimertinib, have improved patient outcomes. However, acquired resistance to these targeted therapies remains a significant challenge, limiting their long-term efficacy. In this new study, Yale Cancer Center researchers at Yale School of Medicine have made a significant development in understanding the mechanisms of resistance to targeted therapies used in the treatment of lung adenocarcinoma driven by EGFR mutations. The study uncovers the role for mammalian SWI/SNF complexes (also known as mSWI/SNF or BAF complexes) in mediating resistance to tyrosine kinase inhibitors. BAF complexes are a group of proteins that remodel the way DNA is packaged.

The new study is a collaboration between investigators at Yale and the Dana Farber Cancer Institute and was published in Cancer Cell on August 3.

"This study has revealed a new vulnerability of a subset of lung adenocarcinomas that have become resistant to standard-of-care targeted therapies,” said , an associate professor of pathology at Yale School of Medicine and member of Yale Cancer Center. “Our findings highlight the importance of epigenetic processes and the role of SWI/SNF complexes in driving osimertinib resistance.”

The research team discovered that mSWI/SNF complexes play a pivotal role in maintaining the gene regulatory profile of osimertinib-resistant lung adenocarcinoma. Impairing the function of mSWI/SNF complexes, either genetically or pharmacologically, resulted in improved osimertinib efficacy, presenting new therapeutic vulnerabilities in osimertinib-resistant lung cancers.

Researchers say the study's findings have significant implications for cancer treatment and precision medicine. Understanding how cancer cells become resistant to targeted therapies—in lung cancer and beyond— is crucial for developing alternative therapeutic approaches for patients.

“This work reveals that chromatin regulatory processes lie at the heart of key clinical challenges in oncology, such as targeted pathway inhibitor resistance,” said co-senior author, Dr. Cigall Kadoch from the Dana-Farber and Harvard Medical School. “Disruption of mammalian SWI/SNF complexes may hold unique promise in combating such resistance, as shown here in a subset of EGFR-mutant Osimertinib resistant lung cancers.”

Politi added, “Epigenetic processes are likely to be responsible for resistance in a significant fraction of lung adenocarcinomas that are resistant to targeted therapies. Identifying them and understanding how they drive resistance is necessary to establish how best to treat these resistant tumors. This study sheds light on one such mechanism.”

Politi and Kadoch are joined by co-first authors Fernando de Miguel at Yale Cancer Center and Claudia Gentile from Dana-Farber Cancer Institute, as well as Yale co-authors , Francisco Expositio, Wesley Cai, Mary Ann Melnick, Camila Robles-Oteiza, Jin Wei, , , Maria Toki, , , , , , and Don Nguyen.