Abstract 3033: Uncovering adaptive mechanisms of resistance to targeted therapy in brain metastasis
Authors: Sally J. Adua, Minghui Zhao, Paul Smith, Darren A. Cross, Don X. Nguyen
Journal: Cancer Research (2019)

Abstract Background A subset of lung adenocarcinoma (LUAD) 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 cellular and molecular causes of resistance to targeted therapies in brain metastasis. Results The efficacy of osimertinib, a brain penetrant third generation TKI, was studied in mice using two different EGFR mutant LUAD models. In the H1975 (EGFR L858R/T790M) model of second-line osimertinib treatment, subcutaneous tumors achieved complete response rates while H1975 brain metastases continued to grow despite strong drug penetrance into the CNS. Similarly, in the PC9 BrM4 (EGFR ex19del) model of first-line osimertinib treatment, most responding animals developed osimertinib resistance preferentially in the brain following significant regression of multi-organ metastatic lesions. Importantly, tumor cells isolated from progressing brain metastases did not exhibit resistance in vitro. However, these cells exhibited significantly enhanced resistant capacity in comparison to controls when serially transplanted into the brain demonstrating both that this resistant phenotype is selected for and that exposure to the brain metastatic niche is a requirement for drug tolerance in vivo. We utilized our recently optimized transcriptomic approach, referred to as Brain Metastasis Xenograft-RNA Sequencing (BMX-seq), to comprehensively distinguish the transcriptome of tumor versus stroma in intact drug resistant brain lesions. Accordingly, our analysis reveals that the stroma of drug resistant brain metastasis is characterized by activation of proinflammatory pathways implying that resistant cells induce and/or co-opt stromal inflammatory responses for their own benefit. Reciprocally, we identified stromal induced alterations in the expression of cytoskeletal and interferon response genes in drug resistant tumor cells. Interestingly, most of these genes are induced by the brain tumor microenvironment (TME) independently of drug treatment suggesting that the brain metastatic niche can precondition tumor cells for ensuing drug resistance. Conclusions Though advances have been made in the brain penetrating abilities of targeted therapies, acquired resistance in this unique metastatic niche still develops. Our results suggest that specific interactions between the tumor cells and stromal cells are required for the manifestation of this adaptive resistant phenotype. Furthermore, transcriptomic profiling has revealed potential regulators and molecular drivers that mechanistically explain how the brain TME preconditions metastatic cells for resistance. Citation Format: Sally J. Adua, Minghui Zhao, Paul Smith, Darren A. Cross, Don X. Nguyen. Uncovering adaptive mechanisms of resistance to targeted therapy in brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3033.