Researchers Identify Vulnerability in Lung Cancers Resistant to Targeted Therapy

Acquired resistance to targeted therapies remains a significant challenge in cancer treatment, limiting their long-term efficacy. A new study by Yale Cancer Center researchers at Yale School of Medicine and the Dana Farber Cancer Institute reports 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 published in Cancer Cell 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.

"This study has revealed a new vulnerability of a subset of lung adenocarcinomas that have become resistant to standard-of-care targeted therapies,” said Katerina Politi, 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.”