NIH Reporter #5P50CA265826-05

Project 2

This NIH/NCI funded project investigates targeted therapies for SMARCA4 mutant lung cancer by exploring replication stress and ATR inhibition, aiming to develop new precision medicine treatments and inform clinical trials.

Description

Loss of function of the SMARCA4/BRG1 gene occurs frequently in lung cancer, yet there is no targeted therapy available for patients with this tumor genotype. Current treatment modalities for these patients are usually ineffective, resulting in death of approximately 16,000 individuals this year in the United States alone. This work will define new precision medicine opportunities for these patients and define how targeting replication stress contributes to therapy response, which will be informative in a wide variety of cancers. The project aims to test the hypothesis that the replication stress associated with BRG1 deficiency provides a therapeutic opportunity for SMARCA4 mutant lung cancer. It will identify drug combinations effective with ATR inhibition, characterize hallmarks of replication stress, assess immune system activation in NSCLC specimens with SMARCA4 mutations, evaluate sensitivity of SMARCA4-mutant NSCLCs to therapies targeting replication stress, and perform pre-clinical studies combining ATR inhibition with immunotherapy. Existing models include CRISPR-generated isogenic BRG1-deficient lines, patient-derived xenografts, and patient samples. The goal is to inform clinical trials exploring novel combination therapies, potentially leading to future approvals.

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