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.