ADRIP · Unraveling mechanisms of drug resistance: APOBEC3A as a genomic and post-transcriptional driver of treatment resistance in pancreatic cancer

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.