CYP2S1 is a synthetic lethal target in BRAFV600E-driven thyroid cancers

Yiqi Li,Nongyue He,Meiju Ji,Peng Hou,Chao Feng,Xi Su,Yue Sun,Haixia Guan,Siyu Liu

doi:10.1038/s41392-020-00231-6

Abstract

BRAFV600E is the most common genetic alteration and has become a major therapeutic target in thyroid cancers; however, intrinsic feedback mechanism limited clinical use of BRAFV600E 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 BRAFV600E 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 BRAFV600E mutation. CYP2S1 knockdown selectively inhibited cell proliferation, migration, invasion and tumorigenic potential in nude mice, and promoted cell apoptosis in BRAFV600E mutated thyroid cancer cells, but not in BRAF wild-type ones. Mechanistically, BRAFV600E-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 BRAFV600E in thyroid cancer cells, thereby causing synthetic lethal interaction between CYP2S1 and BRAFV600E. Finally, we demonstrated CYP2S1 as a potential therapeutic target in both BRAFV600E-drived xenograft and transgenic mouse models by targetedly delivering CYP2S1-specific siRNA. Altogether, our data demonstrate CYP2S1 as a synthetic lethal partner of BRAFV600E in thyroid cancers, and indicate that targeting CYP2S1 will provide a new therapeutic strategy for BRAFV600E mutated thyroid cancers.

Highlights

The incidence rate of thyroid cancer increased rapidly all over the world since the 1970s, until now it has become the most common endocrine malignancy.[1]
The results showed that the expression of HMGCL, CYP2J2, CYP2S1 and CSGLCA-T was significantly elevated in papillary thyroid cancers (PTCs), especially the latter three genes (Fig. 1a, Supplementary Fig. 1) compared to control subjects
Considering that BRAFV600E mutation is found in other types of cancer such as melanomas, colon cancers, and lung adenocarcinomas,[16] we investigated the association of CYP2S1 expression with BRAFV600E mutation in the above cancers

Summary

Introduction

The incidence rate of thyroid cancer increased rapidly all over the world since the 1970s, until now it has become the most common endocrine malignancy.[1]. Synthetic lethal is a kind of interaction between two genes, where only simultaneously perturbing both of the genes can lead to lethality This will provide an alternative paradigm to target “undruggable but important” targets in human cancers.[4] Given that metabolic alterations act as a hallmark of cancer, approaches utilize metabolic properties specific in distinct oncogenic backgrounds can be considered to achieve synthetic lethality in cancer cells.[5,6] A previous study has identified eight potential metabolicrelated synthetic lethality partners of BRAFV600E in melanoma through a high-throughput screening.[7] We analyzed the expression of these genes in PTCs using The Cancer Genome Atlas (TCGA) dataset, and found increased expression of CYP2S1, an orphan cytochrome P450 (CYP) enzyme,[8] in PTCs compared to control subjects. Its expression was strongly associated with BRAFV600E mutation, suggesting that CYP2S1 may be selectively essential in BRAFV600E mutated thyroid cancers

Methods

Results

Conclusion