CYP2S1 is a synthetic lethal target in BRAF^V600E-driven thyroid cancers

BRAF^V600E is the most common genetic alteration and has become a major therapeutic target in thyroid cancers; however, intrinsic feedback mechanism limited clinical use of BRAF^V600E specific inhibitors. Synthetic lethal is a kind of interaction between two genes, where only simultaneously perturbing both of the genes can lead to lethality. Here, we identified CYP2S1 as a synthetic lethal partner of BRAF^V600E in thyroid cancers. First, we found that CYP2S1 was highly expressed in papillary thyroid cancers (PTCs) compared to normal thyroid tissues, particularly in conventional PTCs (CPTCs) and tall-cell PTCs (TCPTCs), and its expression was positively associated with BRAF^V600E mutation. CYP2S1 knockdown selectively inhibited cell proliferation, migration, invasion and tumorigenic potential in nude mice, and promoted cell apoptosis in BRAF^V600E mutated thyroid cancer cells, but not in BRAF wild-type ones. Mechanistically, BRAF^V600E-mediated MAPK/ERK cascade upregulated CYP2S1 expression by an AHR-dependent pathway, while CYP2S1 in turn enhanced transcriptional activity of AHR through its metabolites. This AHR/CYP2S1 feedback loop strongly amplified oncogenic role of BRAF^V600E in thyroid cancer cells, thereby causing synthetic lethal interaction between CYP2S1 and BRAF^V600E. Finally, we demonstrated CYP2S1 as a potential therapeutic target in both BRAF^V600E-drived xenograft and transgenic mouse models by targetedly delivering CYP2S1-specific siRNA. Altogether, our data demonstrate CYP2S1 as a synthetic lethal partner of BRAF^V600E in thyroid cancers, and indicate that targeting CYP2S1 will provide a new therapeutic strategy for BRAF^V600E mutated thyroid cancers.