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

Author

Listed:
  • Sally J. Adua

    (Yale University School of Medicine)

  • Anna Arnal-Estapé

    (Yale University School of Medicine
    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
    Yale University School of Medicine
    Yale University School of Medicine)

  • Veronica Chiang

    (Yale University School of Medicine
    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
    Yale University School of Medicine
    Yale University School of Medicine)

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.

Suggested Citation

  • 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 & , 2022. "Brain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in EGFR-mutant lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34889-z
    DOI: 10.1038/s41467-022-34889-z
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