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

• DOI: 10.1038/s41467-022-34889-z
• Publication Date: 2022-12-12T17:06:28Z
• Authors: Sally J. Adua; Anna Arnal-Estapé; Minghui Zhao; Bowen Qi; Zongzhi Z. Liu; Carolyn Kravitz; Heather Hulme; Nicole Strittmatter; Francesc López-Gi...; Sampada Chande; Alexandra E. Albert; Mary-Ann Melnick; Bomiao Hu; Katerina Politi; Veronica Chiang; Nicola Colclough; Richard J. A. Goo...; Darren Cross; Paul Smith; Don X. Nguyen
• Keywords: Osimertinib

Abstract 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 central nervous system (CNS) relapse in Epidermal Growth Factor Receptor- (EGFR-) mutant non-small cell lung cancer, which can progress when treated with CNS-penetrant EGFR inhibitor osimertinib. Despite widespread osimertinib distribution vivo, microvascular tumor microenvironment (TME) associated persistence of malignant sub-populations, are poised to proliferate as osimertinib-resistant lesions over time. Cellular features this state regulated through Ras homolog family member A (RhoA) Serum Responsive (SRF) gene expression program. RhoA potentiates outgrowth disseminated on treatment, preferentially response extracellular laminin brain. Thus, identify pre-existing adaptive drug-resistant cells, enhanced by RhoA/SRF signaling TME during evolution disease.