The brain tumor microenvironment primes metastatic cells for resistance to targeted therapies

The brain is a major sanctuary site for metastatic lung cancer cells that evade systemic therapies. We performed pharmacological, biological, and molecular studies to identify the functional link between drug resistance and central nervous system (CNS) relapse in late-stage EGFR mutant non-small cell lung cancer, which frequently progresses in the brain even when treated with the brain 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 further proliferate in the brain as osimertinib-resistant lesions over time. Cellular and molecular features of this poised state are commonly regulated through RhoA signaling, which 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 and the brain TME during the evolution of osimertinib resistant disease. Overall design: Species specific RNA-seq performed in control (C2) and resistant (R2) human cell populations growing in mouse brain when treated with vehicle or osimertinib. There are 6 in vivo sample groups each with 3-4 reps. The same control and resistant cell populations growing in culture and treated with vehicle or osimertinib were also sent for sequencing (3 reps each).