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Paul Smith

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    MA09 - EGFR & MET (ID 128)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA09.06 - Adaptive Mechanisms of Resistance to Targeted Therapy in EGFR Mutant Brain Metastasis (Now Available) (ID 1329)

      15:15 - 16:45  |  Author(s): Paul Smith

      • Abstract
      • Presentation
      • Slides


      A subset of non-small cell lung cancers (NSCLCs) can be effectively treated with EGFR tyrosine kinase inhibitors (TKIs). However, a significant proportion of patients with brain metastasis progress after front-line treatment, underscoring the central nervous system (CNS) as a unique sanctuary site for persistent disease. Herein, we performed an integrated examination of the cellular, pharmacological, and molecular causes of resistance to targeted therapies in brain metastases.


      The efficacy of osimertinib, a brain penetrant third generation TKI, was studied in mice using EGFR mutant NSCLC models derived from cell lines or patient biopsies. Animals with multi-organ metastases were treated continuously until disease progression was detected in the brain parenchyma. We also developed an in situ transcriptomic approach, referred to as Brain Metastasis Xenograft-RNA Sequencing (BMX-seq), to distinguish the transcriptome of tumor versus stroma in vivo. Molecular and biological responses were integrated with pharmacological analysis of loco-regional distribution of osimertinib in and around brain lesions.


      In EGFR mutant models with multi-organ metastases, extra-cranial tumors could be effectively controlled, while brain metastases eventually progress despite strong osimertinib penetrance into the normal and tumor bearing CNS. Importantly, tumor cells isolated from progressing brain metastases did not exhibit resistance in vitro. However, these cells exhibited an enhanced resistant capacity when transplanted into the brain, demonstrating that this resistant phenotype is selected for and that exposure to the brain is a requirement for drug resistance in vivo.

      BMX-seq reveals that the stroma of drug resistant brain metastasis is characterized by activation of innate pro-inflammatory pathways. Reciprocally, we identified stromal induced activation of cytoskeletal and interferon response genes in drug resistant tumor cells. Interestingly, several of these genes are induced in situ independently of drug treatment, suggesting that the brain metastatic niche can precondition tumor cells for ensuing drug resistance. Finally, we demonstrate that inhibiting mediators of interferon and cystoskeletal signaling increases the sensitivity of brain metastasis to osimertinib in vivo.


      Although advances have been made in the brain penetrating abilities of targeted therapies, acquired resistance in this unique TME still develops. Our results suggest that adaptive molecular interactions within the brain TME preconditions metastatic cells for TKI resistance and that targeting such pathways in combination with osimertinib should be explored to treat NSCLC patients suffering from or at risk for brain relapse.

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