Abstract B056: SOAT1 inhibition by a covalent metabolite mimetic targets RAS maturation and pancreatic cancer
Wenjun Lan, Shoujun Sun, Nitin Pawar, Jérémy Nigri, Juliene Hinds, Astrid Deschênes, Lesley Ferguson, Cristina Lopez, Sangjun Yoon, Yijian Qiu, Victoria Gaeth, Sara Pawlak, Clementina Strozek, Michelle Saoi, Ritchie Ly, Shaheen Khan, Rachel Rubino, Youngkyu Park, Scott Lyons, Adam Moorhouse, Michael Lukey, Shozeb Haider, Hiro Furukawa, Paolo Cifani, Justin Cross, Michael Murphy, John Moses, David TuvesonAbstract
Oncogenic KRAS requires prenylation for membrane localization and cellular transformation, but extensive efforts to inhibit this process for cancer therapy have failed. We report that Sterol o-acyl transferase 1 (SOAT1) stimulates Pancreatic Ductal Adenocarcinoma (PDAC) cells by enhancing isoprenoid synthesis to increase RAS membrane localization and mitochondrial function. Acute loss of SOAT1 attenuates PDAC transformation, nominating the therapeutic potential of targeting this non-essential enzyme. Since existing SOAT1 inhibitors lacked selectivity in PDAC cells, we developed SOAT1 covalent metabolite mimetic antagonists. Our lead compound elicits SOAT1 degradation and collapses RAS signaling and mitochondrial function in PDAC cells, demonstrating potent anti-neoplastic activity while sparing normal tissues in multiple murine PDAC models. Therefore, SOAT1 targeting provides a new means to attenuate RAS maturation and oncogenicity in PDAC.
Citation Format:
Wenjun Lan, Shoujun Sun, Nitin Pawar, Jérémy Nigri, Juliene Hinds, Astrid Deschênes, Lesley Ferguson, Cristina Lopez, Sangjun Yoon, Yijian Qiu, Victoria Gaeth, Sara Pawlak, Clementina Strozek, Michelle Saoi, Ritchie Ly, Shaheen Khan, Rachel Rubino, Youngkyu Park, Scott Lyons, Adam Moorhouse, Michael Lukey, Shozeb Haider, Hiro Furukawa, Paolo Cifani, Justin Cross, Michael Murphy, John Moses, David Tuveson. SOAT1 inhibition by a covalent metabolite mimetic targets RAS maturation and pancreatic cancer [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B056.