New hope for patients with resistant lung cancer

Understanding the mechanism: BAF complexes and resistance to tyrosine kinase inhibitors.


In a groundbreaking study, researchers have made a significant discovery regarding lung cancers that develop resistance to targeted therapies. Despite the effectiveness of tyrosine kinase inhibitors (TKIs) like Osimertinib in treating certain types of lung cancer, resistance to these drugs has been a significant challenge. However, the latest findings shed light on a potential vulnerability in these resistant cancer cells, offering new hope for improved treatment strategies.

In a recent study, researchers from Yale Cancer Center and Dana Farber Cancer Institute have made a significant breakthrough in understanding the resistance mechanisms to targeted therapies for lung adenocarcinoma driven by EGFR mutations.

Researchers discovered that mammalian SWI/SNF complexes, also known as BAF complexes, play a key role in mediating resistance to tyrosine kinase inhibitors (TKIs) like Osimertinib. Despite the success of targeted therapies in cancer treatment, acquired resistance remains a challenge, making this finding a promising step toward improving long-term efficacy in lung cancer patients. The study was published in Cancer Cell on August 3.

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

The research team’s significant discovery reveals that mSWI/SNF complexes play a crucial role in maintaining gene regulation in osimertinib-resistant lung adenocarcinoma. Impairing the function of these complexes, either genetically or pharmacologically, enhances osimertinib efficacy, unveiling new therapeutic vulnerabilities in resistant lung cancers.

The researchers findings have important implications for cancer treatment and precision medicine, offering a potential strategy to combat resistance to targeted therapies in specific EGFR-mutant osimertinib-resistant lung cancers.

The study highlights the importance of understanding chromatin regulatory processes in addressing clinical challenges in oncology, and disrupting mSWI/SNF complexes holds promise in overcoming resistance.

Identifying epigenetic processes that drive resistance in lung adenocarcinomas without response to targeted therapies is essential for devising effective treatments, and this research sheds light on one such mechanism involving mSWI/SNF complexes.

The research findings signify a significant breakthrough in the fight against drug-resistant lung cancers. By identifying the role of BAF complexes in mediating resistance to Osimertinib and other TKIs, this study opens up new avenues for developing innovative treatment approaches. Further studies and clinical trials are warranted to explore the potential of targeting BAF complexes in overcoming drug resistance and improving the prognosis of patients with lung cancer.

Journal Reference:

  1. Fernando J. de Miguel, Katerina A. Politi et al., Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer. Cancer cell. DOI: 10.1016/j.ccell.2023.07.005.


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