Brain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in EGFR-mutant lung cancer

The brain is a major sanctuary site for metastatic cancer cells that evade systemic therapies. Through pre-clinical pharmacological, biological, and molecular studies, we characterize the functional link between drug resistance and central nervous system (CNS) relapse in Epidermal Growth Factor Receptor- (EGFR-) mutant non-small cell lung cancer, which can progress in the brain when treated with the CNS-penetrant EGFR inhibitor osimertinib. Despite widespread osimertinib distribution in vivo, the brain microvascular tumor microenvironment (TME) is associated with the persistence of malignant cell sub-populations, which are poised to proliferate in the brain as osimertinib-resistant lesions over time. Cellular and molecular features of this poised state are regulated through a Ras homolog family member A (RhoA) and Serum Responsive Factor (SRF) gene expression program. RhoA potentiates the outgrowth of disseminated tumor cells on osimertinib treatment, preferentially in response to extracellular laminin and in the brain. Thus, we identify pre-existing and adaptive features of metastatic and drug-resistant cancer cells, which are enhanced by RhoA/SRF signaling and the brain TME during the evolution of osimertinib-resistant disease. While EGFR-targeted therapies have clinical benefit, drug-resistant brain metastases present a major obstacle. Here, the authors identify a genetic signature in brain metastatic lesions associated with osimertinib resistance and find RhoA to have an important role in the resulting phenotype.

Automated summary

The brain acts as a sanctuary site for metastatic cancer cells that can evade systemic therapies. In this study, the authors investigate the functional connection between drug resistance and central nervous system relapse in EGFR-mutant non-small cell lung cancer. They find that the brain microvascular tumor microenvironment is associated with the persistence of malignant cell sub-populations, which can proliferate in the brain as osimertinib-resistant lesions. This resistance is regulated by the RhoA/SRF signaling pathway. The authors also identify a genetic signature associated with osimertinib resistance in brain metastatic lesions.