O28: M6A DEMETHYLASE FTO A POTENTIAL TARGET IN BRAIN METASTATIC BREAST CANCER

Abstract Introduction Brain metastasis (BrM) occurs in 10-30% of patients with advanced breast cancer (BC). BrM is increasing incidence and confers a poor prognosis. We aimed to investigate the contribution global epi-transcriptomic alterations N6-methyladenosine (m6A) RNA-methylation as therapeutic target brain metastatic cancer. Method In preliminary studies we have demonstrated m6A demethylase – FTO main contributor progression ER+ Furthermore an association between reduced disease-free-survival (n=870, p=0.018) was observed. Here conducted epigenetic inhibitor screen using two agents, ethyl-ester-meclofenamic acid (MA2) FB23-2 on matched 2D cell line, 3D organoid cultures patient-derived xenografts (PDX) explant models metastasis. Result Upon integration mapped RNA methylation landscape proteomic analysis, observed genome-wide hypo-methylation key pluripotency genes, including SOX2 KLF4, players underlying tumour brain. Genetic pharmacological inhibition novel ex vivo significantly protein expression levels KLF4 SOX2. Moreover, MA2 FB23-2, inhibited proliferation endocrine-resistant BC patient cells. translate our findings clinic by demonstrating efficacy anti-FTO therapies several unique PDX models. Conclusion Our results reveal epi-transcriptional remodelling events mechanism BrM. This study establishes early role for targeting management disease presents potential Take-home message