Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA, 02139, USA.
Shanghai ChemPartner Co. Ltd., 998 Halei Road, Pudong, 201203, Shanghai, China.
Nat Commun. 2019 Jan 9;10(1):96. doi: 10.1038/s41467-018-07959-4.
Aberrant metabolism of cancer cells is well appreciated, but the identification of cancer subsets with specific metabolic vulnerabilities remains challenging. We conducted a chemical biology screen and identified a subset of neuroendocrine tumors displaying a striking pattern of sensitivity to inhibition of the cholesterol biosynthetic pathway enzyme squalene epoxidase (SQLE). Using a variety of orthogonal approaches, we demonstrate that sensitivity to SQLE inhibition results not from cholesterol biosynthesis pathway inhibition, but rather surprisingly from the specific and toxic accumulation of the SQLE substrate, squalene. These findings highlight SQLE as a potential therapeutic target in a subset of neuroendocrine tumors, particularly small cell lung cancers.
癌细胞的代谢异常是众所周知的，但确定具有特定代谢脆弱性的癌症亚群仍然具有挑战性。我们进行了化学生物学筛选，发现了一组神经内分泌肿瘤，它们对胆固醇生物合成途径酶鲨烯环氧化酶（SQLE）的抑制表现出显著的敏感性。通过各种正交方法，我们证明对 SQLE 抑制的敏感性不是来自胆固醇生物合成途径的抑制，而是出人意料地来自 SQLE 底物鲨烯的特异性和毒性积累。这些发现突出了 SQLE 作为神经内分泌肿瘤亚群（特别是小细胞肺癌）的潜在治疗靶点。
