tRNA dosage regulates lineage dependency and resistance in prostate cancer

Lineage plasticity underlies therapeutic resistance in cancer^1,2, yet the translational mechanisms that enable this phenotypic flexibility remain largely unknown. Here using prostate cancer as a model of lineage dependence, we performed unbiased small RNA sequencing and identified tRNA₁^Arg(UCU) as a regulator of lineage transitions and therapy resistance. tRNA₁^Arg(UCU) is capable of reprogramming lineage dependence, which can be tuned to restore sensitivity to therapies that target the androgen receptor. We identify TARDBP and ZSCAN29 as DNA-binding proteins that directly engage the genomic locus of tRNA₁^Arg(UCU) to regulate its expression, a result that highlights the importance of non-canonical tRNA-specific gene regulation. Mechanistically, tRNA₁^Arg(UCU) controls a translational program centred on SWI/SNF chromatin remodellers, which is necessary to maintain lineage fidelity. In patients, tRNA₁^Arg(UCU) is downregulated in neuroendocrine prostate cancer and its loss is associated with accelerated metastasis and poor survival. These findings uncover a previously unrecognized tRNA-specific regulatory axis that links codon biology to lineage dependence and therapy resistance in prostate cancer.