Abstract
It is estimated that one-third of EGFR-mutant lung cancer patients develop brain metastasis during the course of their disease. Brain metastasis is associated with a significant decline in cognitive and motor function, daily functioning, and accelerated mortality. Brain metastasis is a severe complication for 45% of patients with EGFR-mutant lung cancer that drastically reduces their quality of life and survival. Fortunately, EGFR-tyrosine kinase inhibitors (TKIs) such as osimertinib showed excellent blood-brain-barrier permeability and resulted in dramatic responses in patients with brain metastases. However, despite a striking initial response, osimertinib-treated patients eventually develop relapse, often to the brain, and succumb to death. With this fatal malignancy, it is important to understand underlying mechanisms of brain metastasis to improve treatment outcomes, which is an unmet need in the field. To study mechanisms of brain relapse, we generated osimertinib treatment-response-and-relapse mouse models using human lung cancer cells harboring osimertinib-sensitive EGFR-activating mutations. Using these new brain relapse models of EGFR-mutant lung cancer, we identified that a S100A9-ALDH1A1-RA signaling axis endows cancer cells with the ability to thrive in the brain despite on-target inhibition of EGFR activity by osimertinib. Mechanistically, we show that S100A9 upregulates ALDH1A1 expression and activate the retinoic acid (RA) signaling pathway in cancer cells, which promotes brain relapse. We demonstrate that the genetic repression of S100A9, ALDH1A1, or retinoic acid receptor (RAR) in cancer cells, or treatment with a pan-retinoic-acid-receptor antagonist, dramatically reduces brain metastasis in independent preclinical models of brain relapse. Importantly, S100A9 expression in cancer cells correlates with poor PFS in patients on osimertinib. Based on these preclinical findings, we propose that RAR antagonist treatment can be tested in patients to target osimertinib-resistant brain metastases. Notably, intracellular S100A9 expression in cancer cells can be used as a biomarker to stratify patients who might benefit from this combination treatment.