PRMT5 inhibitors actively promote metastatic progression of lung adenocarcinoma.

Epigenetic changes are a major driver of cancer progression, placing considerable focus on epigenetic regulators as therapeutic targets. Protein arginine methyltransferase 5 (PRMT5) is one such regulator, and numerous PRMT5 inhibitors (PRMT5i) in clinical trials. Despite this, the mechanisms and consequences of PRMT5i-resistance are unknown. Here, we demonstrate that aggressive cancer progression is an inbuilt feature of PRMT5i-resistance acquisition in lung adenocarcinoma (LUAD). Independently-generated resistant cell lines gain dedifferentiation signatures that typify late-stage disease and show increased metastatic potential in vivo. We establish that these state shifts are a direct consequence of PRMT5i action; treatment induces rapid and widespread chromatin rewiring, enabling derepression of late-stage disease states that are stably established in resistant cells. Notably, treatment of lung tumor-bearing mice drives rapid disease advancement without decreasing tumor burden, showing that drug-induced disease progression supersedes any benefits from PRMT5 inhibition in vivo. Furthermore, analyses of human cell lines and patient cohorts supports the notion of PRMT5 inhibition-mediated dedifferentiation. Collectively our data show that PRMT5i can actively promote self-resistance and disease progression in different tumor types. This raises serious concerns for the use of PRMT5i in patients, arguing that clinical studies should consider the possibility of drug-induced plasticity, resistance, and disease advancement.