Targeting the Sterol Regulatory Element-Binding Protein (SREBP) Pathway in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with limited diagnostic and therapeutic options. Due to its proliferative nature and thick, desmoplastic stroma, PDAC tumor cells are challenged with meeting a high demand for lipids in a hypoxic, lipid-poor environment. Cancer cells respond to changes in lipid conditions through sterol regulatory element-binding proteins (SREBPs). SREBPs are central transcriptional regulators of lipid homeostasis and require SREBP cleavage activating protein (SCAP) during signaling. While the SREBP pathway has been implicated in several other malignant cancers, its role in PDAC and utility as a therapeutic target has not been studied. Here, we find that SREBP target genes and pathways related to lipid synthesis and uptake are upregulated in PDAC in response to alterations in the lipid environment. Pharmacological inhibition of the SREBP pathway in low lipid conditions revealed a strong reliance on the SREBP pathway for tumor cell growth and survival. Loss of SCAP in PDAC tumor cells alters the growth capability both in vitro and in vivo using preclinical xenograft mouse models. Heterozygous loss of Scap in the KPC mouse model significantly increased survival. Additionally, mice with a homozygous loss of Scap did not develop invasive PDAC compared to KPC mice. In human PDAC cells and patient-derived organoids, dipyridamole, an SREBP pathway inhibitor, synergized with statins to promote tumor cell death in a mevalonate-dependent and phosphodiesterase-independent manner. Finally, KPC mice demonstrate clinically relevant pathologic phenotypes that impact the lifespan of the animal and interpretation of preclinical data. Together, these data establish that 1) the SREBP pathway is a viable therapeutic target for PDAC, 2) the combination therapy of FDA-approved compounds dipyridamole and statins potentiates PDAC cell death in vitro, and 3) off-target pathology of the KPC mouse model warrants judicious use as a genetically engineered mouse model of pancreatic cancer