Dual mTORC1/2 and Scd1 inhibition uncovers a therapeutic vulnerability in pancreatic cancer

Abstract Hyperactivation of the mechanistic target of rapamycin (mTOR) complexes, mTORC1 and mTORC2, is common in pancreatic ductal adenocarcinoma (PDAC). However, clinical use of mTOR inhibitors has shown limited efficacy due to rapid adaptive resistance. Using inducible genetically engineered mouse models and matched organoids, we delineated distinct complex-specific adaptations. Loss of mTORC1 delayed tumor progression but induced compensatory PI3K/Akt signalling hyperactivation, while concurrently suppressing inflammatory cancer-associated fibroblasts and desmoplasia through Il-1ra. In contrast, mTORC2 loss impaired de novo sphingolipid synthesis, shifted lipid composition toward saturation, increased the saturated-to-monounsaturated fatty acid ratio, enriched plasma membrane lipid rafts, and amplified interferon-γ signaling. This lipid reprogramming generated a synthetic-lethal dependency on stearoyl-CoA desaturase 1 (Scd1). Pharmacological co-inhibition of mTORC1/2 and Scd1 prevented adaptive PI3K/Akt signalling rebound, remodelled the tumor stroma, enhanced interferon-γ responses, and synergized with anti-PD-1 therapy. These findings establish dual targeting of mTOR signaling and Scd1 as a rational therapeutic strategy for PDAC.