Mechanisms of Heterogeneous Targeted Therapy Response in Brain Metastasis

Abstract

A subset of lung adenocarcinomas (LUADs) can be effectively treated with EGFR tyrosine kinase inhibitors (TKIs). However, the incidence of brain metastasis increases in patients that relapse after front line treatment, underscoring the central nervous system (CNS) as a unique sanctuary site for persistent disease. We sought to perform an integrated examination of the physiological, cellular, and molecular causes of mixed therapeutic responses in brain metastasis. The efficacy of a third generation brain penetrant TKI, osimertinib, was studied in mice using two different EGFR mutant LUAD models of multi organ metastasis. A combination of live imaging modalities was employed to assess the location and kinetics of osimertinib responses in vivo. While complete responses could be achieved in subcutaneous tumors, mixed responses to osimertinib were often observed in metastatic tumors that had colonized regions of the brain or extra-cranial tissues. Moreover, following significant regression of certain metastatic lesions, most responding animals develop resistance, preferentially in the brain despite strong CNS drug penetration. Finally, tumor cells isolated from progressing brain metastases do not exhibit resistance in vitro suggesting that exposure to the brain metastatic niche is a requirement for drug tolerance in vivo. We established a clinically relevant approach to study the multi-factorial causes of osimertinib response heterogeneity in the in vivo metastatic setting.