Therapeutic genome screen in AsPC1

Pancreatic adenocarcinoma generally does not respond to our current therapeutic approaches of surgical resection, radiation and chemotherapy with an overall five-year survival of only 8%. In an effort to identify potential new therapeutic approaches for pancreatic cancer, we carried out a targeted synthetic lethal CRISPR screens in the pancreatic cell line AsPC1. A custom CRISPR knockout library, termed the Therapeutic Genome (RxG) Library, which targets genes for which a current drug already exists was utilized in the screens. We used the RxG library to identify genes and corresponding gene products which modulate the sensititive and resistance to three chemotherapeutics, Gemcitabine, 5-fluorouracil, and Niraparib in the AsPC1 cell line. This screen identified multiple gene products which potentiate sensitivity to these three chemotherapeutics, and in particular, BCL2L1 which encodes BCL-xL, was identified as a common genetic factor that when mutant, enhances sensitivity to all three drugs. A novel drug, DT2216, in Phase I clinical trials which targets BCL-xL for degradation was shown to enhance the effectiveness of Gemcitabine in additional pancreatic cancer cell lines as well as patient-derived xenograft models without enhanced systemic toxicity. This work supports a possible utility of combined Gemcitabine/DT2216 as a novel therapy for pancreatic cancer.