Lan, Wenjun, Sun, Shoujun, Nigri, Jeremy, Homer, Josh, Park, Young, Deschenes, Astrid, Cifani, Paolo, Cross, Justin, Gaeth, Victoria, Kim, Sunny, Ting, Shawn, Rubino, Rachel, Moses, John, Tuveson, David (January 2024) SOAT1 as a targetable KRAS dependency in PDAC. In: AACR Special Conference in Cancer Research: Pancreatic Cancer, 2023 Sep 27-30, Boston, Massachusetts.
Abstract
Metabolic rewiring is an emerging hallmark of neoplasia. In pancreatic ductal adenocarcinoma (PDAC), KRAS alters myriad metabolic programs to promote cellular transformation. Among them, the cholesterol synthesis pathway has emerged as a vulnerability of cancer cells due to the importance of cholesterol in membrane fluidity and the production of isoprenoid intermediates that enable KRAS membrane localization and activation in pancreatic cancer. We recently reported that the non-essential gene SOAT1 (Sterol-O-Acyl transferase 1), encoding an enzyme that esterifies free cholesterol into an insoluble form for storage and transport, is markedly upregulated in metastatic PDAC cells. SOAT1 promotes the hyperactivation of the mevalonate synthesis pathway due to loss of negative feedback by free cholesterol, thereby leading to increased production of isoprenoids such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which are required for RAS and RHO membrane localization and activity, respectively. Genetic ablation of Soat1 reduced RAS and RHO membrane localization and inhibited cellular proliferation and mitochondrial function in vitro, and these effects were largely rescued by exogenous FPP and GGPP. Therefore, our study nominated SOAT1 as a new candidate gene for therapeutic targeting. Based on SuFEx Click Chemistry (ASCC) technology, we have designed and synthesized a panel of drug-like candidates. The first series of Soat1 probes selectively impair the proliferation of PDAC cells that express SOAT1, reduce SOAT1 protein content in cells, and covalently bind to SOAT1. In mice, the most active SOAT1 probes were tolerated in a 28-day daily dosing study up to 120 mg/kg. Marked tumor growth inhibition was noted in mice bearing PDAC xenografts and GEMM mice treated as monotherapy with 15 mg/kg/d of the most active SOAT1 probe, and tissue analysis demonstrated tumor necrosis, decreased proliferation, and increased apoptosis. Mechanistically, SOAT1 loss or inhibition targets multiple important components of cellular transformation in PDAC including KRAS, RHO, and mitochondrial biology, and our work suggests that it is an attractive target to pursue for further drug development in this cancer.
| Item Type: | Conference or Workshop Item (Paper) |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Tuveson lab CSHL labs > Moses lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 16 January 2024 |
| Date Deposited: | 11 Mar 2024 17:32 |
| Last Modified: | 11 Mar 2024 17:32 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41459 |
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