Thursday, June 12, 2025
6/12/2025
Targeting iron metabolism in pancreatic adenocarcinoma to overcome KRAS inhibitor therapeutic resistance - PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is the third most common cause of cancer-related death in the US with dismal five-year survival rates of 13%. KRAS is the dominant oncogene in PDAC and is mutated in ~90% of tumors. While considered undruggable for over 40 years, recent advances have led to the development of mutant allele-specific KRAS and pan-RAS inhibitors (KRASi) that demonstrate activity in PDAC patients in early clinical trials. However, resistance is a near-universal feature of targeted therapies. Therefore, there is an urgent need to understand how to effectively implement KRAS inhibition to prevent resistance and maximally benefit patients. Through this research plan, we will define the iron and autophagy-dependent mechanisms of KRASi resistance and identify novel KRASi combinatorial approaches targeting iron metabolism to overcome resistance. The rationale for this approach is based on our prior work defining PDAC dependency on a pathway that links iron metabolism and autophagy called ‘ferritinophagy’, whereby a selective autophagy receptor, NCOA4, targets ferritin, the cellular iron storage complex, to the lysosome for ferritin degradation and release of iron to the cytosol for utilization. Furthermore, our preliminary data suggests that PDAC upregulate ferritinophagy-mediated iron supply to sustain mitochondrial metabolism and proliferation after acute KRASi and in long-term epithelial-to-mesenchymal transition associated KRASi resistance. However, iron addiction is a double-edged sword as iron increases susceptibility to ferroptosis, an iron-dependent form of cell death. Therefore, a key approach in targeting KRASi resistance may be to disrupt iron metabolism by ‘starving’ tumor cells of iron or, conversely, by promoting iron-dependent ferroptosis. The overarching hypothesis of this proposal is that disrupting iron homeostasis in PDAC by either iron depletion (ferritinophagy inhibition) or iron overload (ferroptosis induction) in combination with KRAS inhibition represents an anti-PDAC therapeutic strategy. We will evaluate this hypothesis in three aims: 1) to define dysregulated ferritinophagy and iron metabolism as mechanisms of acute adaptive resistance in PDAC to KRASi, 2) to target epithelial-to-mesenchymal transition and iron metabolism as non-genetic mechanisms of long-term acquired resistance to KRASi in PDAC, and 3) to target KRASi resistance by ferroptosis induction. To accomplish our aims, we will leverage our scientific expertise in autophagy, iron metabolism and pancreatic cancer and our technical expertise in quantitative proteomics, cell biology, and patient-derived and mouse models of PDAC. Furthermore, we have assembled a collaborative team with complementary expertise in PDAC genetics and translational models, PDAC clinical trial correlative science, the chemical biology of cellular iron sensing, ferroptosis, and in novel chemistry for targeting cancer iron metabolism. Deciphering the relevant iron acquisition pathways and iron-dependent functional requirements that can mediate KRAS inhibitor resistance in PDAC may identify new therapeutic targets and combination therapies, which is critical for patients with PDAC given the lack of effective treatment options for this devastating disease.
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