Abstract 62P
Background
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a 5-year survival rate of 13%, mainly due to late diagnosis and treatment resistance. KRAS mutations play a central role in PDAC, and while the PI3K pathway and PDK1 can be targeted, resistance mechanisms limit treatment efficacy. Identifying these mechanisms is critical to improving therapies.
Methods
This study employed a robust genome-wide CRISPR activation (CRISPRa) gain-of-function screen to identify genetic pathways conferring resistance to PDK1 deletion in KRAS-driven PDAC. Using a CRISPRa SAM library of 23,439 genes, we activated genes in a KRASG12D-mutant murine PDAC cell line, assessing survival after PDK1 deletion via a Cre/loxP system, confirmed by PCR. Bioinformatics analysis then identified enriched pathways and key genetic drivers of resistance.
Results
The CRISPRa screen identified several resistance-associated signaling pathways, including ErbB, PI3K-AKT-mTOR, JAK/STAT, and Hippo/YAP1 pathways. Further pathway analysis revealed key genetic drivers, highlighting ErbB2/3, Rptor, Akt1, and Stat1. Conversely, TGF-beta signaling was depleted in PDK1-deleted cells. Targeting pathways like ErbB and PI3K-AKT-mTOR, both established in therapeutic contexts, could potentially synergistically enhance PDK1-targeted therapy efficacy. Preliminary data validate the role of mTOR signaling and TGF-beta’s impact on PDAC cell survival with PDK1 inhibition.
Conclusions
These findings provide valuable insights into the functional genetic basis of therapy resistance in PDAC. The identified pathways, including ErbB, PI3K-AKT-mTOR, JAK/STAT, Hippo/YAP1, and TGF-beta represent potential targets for combinatorial drug treatments to overcome resistance to PDK1 inhibition. Future work will focus on validating these targets through drug treatment assays and exploring their clinical relevance in improving PDAC treatment outcomes.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Technical University Munich, Munich, Germany.
Funding
The study was funded by the German Research Foundation and supported by the Else Kröner Promotionskolleg by the Technical University of Munich.
Disclosure
All authors have declared no conflicts of interest.