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.