CYP2S1 is a synthetic lethal target in BRAFV600E-driven thyroid cancers
Yiqi Li, Xi Su, Chao Feng, Siyu Liu, Haixia Guan, Yue Sun, Nongyue He, Meiju Ji, Peng Hou
Abstract
Abstract 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.