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

Sally J. Adua, Anna Arnal-Estapé, Minghui Zhao, Bowen Qi, Zongzhi Z. Liu, Carolyn Kravitz, Heather Hulme, Nicole Strittmatter, Francesc López-Giráldez, Sampada Chande, Alexandra E. Albert, Mary-Ann Melnick, Bomiao Hu, Katerina Politi, Veronica Chiang, Nicola Colclough, Richard J. A. Goodwin, Darren Cross, Paul Smith and Don X. Nguyen ()
Additional contact information
Sally J. Adua: Yale University School of Medicine
Anna Arnal-Estapé: Yale University School of Medicine
Minghui Zhao: Yale University School of Medicine
Bowen Qi: Yale University School of Medicine
Zongzhi Z. Liu: Yale University School of Medicine
Carolyn Kravitz: Yale University School of Medicine
Heather Hulme: Clinical Pharmacology and Safety Sciences, AstraZeneca
Nicole Strittmatter: Clinical Pharmacology and Safety Sciences, AstraZeneca
Francesc López-Giráldez: Yale University School of Medicine
Sampada Chande: Yale University School of Medicine
Alexandra E. Albert: Yale School of Medicine
Mary-Ann Melnick: Yale University School of Medicine
Bomiao Hu: Yale University School of Medicine
Katerina Politi: Yale University School of Medicine
Veronica Chiang: Yale University School of Medicine
Nicola Colclough: Early Oncology TDE, AstraZeneca
Richard J. A. Goodwin: Clinical Pharmacology and Safety Sciences, AstraZeneca
Darren Cross: Global Oncology Medical Affairs, AstraZeneca
Paul Smith: Bioscience, Early Oncology TDE, AstraZeneca
Don X. Nguyen: Yale University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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 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.

Date: 2022
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DOI: 10.1038/s41467-022-34889-z

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