Project description
Investigating drug resistance in pancreatic cancer
Pancreatic cancer is projected to become the third leading cause of cancer-related deaths in Europe due to drug resistance in pancreatic ductal adenocarcinoma (PDAC). Kirsten rat sarcoma virus (KRAS) mutations occur in over 90 % of cases. The APOBEC3A (A3A) family of enzymes contributes to mutagenesis and drug resistance. The ERC-funded ADRIP project will investigate A3A’s role in increasing intratumoral heterogeneity (ITH) in PDAC using murine and human models. It will determine if A3A contributes to both existing and acquired resistance to KRAS inhibitors through genomic or post-translational modifications. The study will apply a multi-omics approach to identify novel A3A regulators as potential therapeutic targets, informing future pre-clinical and clinical trials aimed at combating drug resistance in KRAS.
Objective
Pancreatic cancer is predicted to become the third leading cause of cancer-related death in Europe. Drug resistance to even the most effective anti-cancer-targeted therapies constitutes a major contributor to poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Kirsten rat sarcoma virus (KRAS) mutations are found in >90% of PDAC, being an important oncogenic driver. Although KRAS-targeted therapies have the potential to transform the clinical management of PDAC drastically, only a subset of patients respond, and resistance is frequent. The extent to which genomic and post-translational processes drive drug resistance remains largely unknown. Genomic analyses have identified the APOBEC family as a key driver of mutagenesis in cancer, including PDAC. Among family members, APOBEC3A (A3A) is involved in genomic alteration and post-transcriptional RNA editing, both mechanisms causative for intra-tumoral heterogeneity (ITH) and drug resistance. My preliminary data reveal that A3A induces chromosomal instability and likely ITH. In addition, I found that A3A-mediated RNA editing is prevalent in human PDACs and a mouse model for A3A. Importantly, I observed that A3A expression increases during KrasG12D targeted therapy, reduces sensitivity, and facilitates clonal outgrowth, and thus, is likely to drive drug resistance in PDAC. The ADRIP study will utilize murine and human models for A3A, to unravel for the first time whether A3A plays a dominant role in increasing ITH in PDAC (Aim1). Second, it will elucidate whether A3A-mediated genomic or post-translational modifications (Aim2) drive pre-existing and acquired KRAS inhibitor resistance. Applying a multi-omics approach, the ADRIP study aims to identify novel regulators of A3A that could serve as therapeutic targets (Aim3). Importantly, the ADRIP study may have direct clinical implications as the basis for future pre-clinical/clinical intervention trials that target A3A to prevent drug resistance in KRAS mutant cancers.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. This project's classification has been validated by the project's team.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. This project's classification has been validated by the project's team.
Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
81675 MUENCHEN
Germany