Harnessing lipid metabolism to treat drug-tolerant persister cells

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, with a five-year survival rate of only 13% and limited response to current therapies. A major contributor to treatment failure is the emergence of drug-tolerant persister cells (DTPs), a slow-cycling subpopulation that survives targeted and systemic therapy and drives relapse. Here, we aimed to determine whether the metabolic dependencies of DTPs could be exploited to eliminate these cells. Through analysis of publicly available transcriptomic datasets across multiple malignancies, including PDAC, colorectal, breast, and non-small cell lung cancers, we identified consistent downregulation of SREBF1 , a master regulator of de novo lipid synthesis, in DTPs. We previously demonstrated that PDAC cells with impaired lipogenesis are selectively vulnerable to exogenous polyunsaturated fatty acids (PUFAs) due to their inability to balance saturated and monounsaturated fatty acid pools, resulting in ferroptotic death. Based on these findings, we hypothesized that DTPs can be targeted through PUFA overload. To test this, we induced DTPs in murine PDAC cell lines using the KRAS-targeted therapy RMC-7977 and treated them with PUFAs, including alpha-eleostearic acid (ESA). ESA supplementation was sufficient to eradicate PDAC DTPs at dietarily achievable concentrations. We are now evaluating whether this approach can limit relapse by targeting minimal residual disease in animal models of PDAC treated with KRAS inhibitors. These findings reveal a diet-based strategy that exploits metabolic vulnerabilities of therapy-persistent PDAC cells and may reduce the risk of disease recurrence.