Integrative genomic identification of therapeutic targets for pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, and new therapeutic strategies are urgently needed. Here, we conduct an integrative, genome-scale examination of genetic dependencies and cell surface targets using CRISPR-Cas screening and multi-omic data, including single-nucleus and spatial transcriptomic data from patient tumors. We systematically identify clinically tractable and biomarker-linked PDAC dependencies, including CDS2 as a synthetic lethal target in cancer cells expressing signatures of epithelial-to-mesenchymal transition. We examine biomarkers and co-dependencies of the KRAS oncogene, defining gene expression signatures of sensitivity and resistance associated with response to pharmacological inhibition of KRAS. mRNA and protein profiling reveal cell surface protein-encoding genes with robust expression in patient tumors and minimal expression in non-malignant tissues. Furthermore, we define intratumoral and interpatient heterogeneity of target gene expression and identify orthogonal targets that suggest combinatorial strategies. Collectively, this work identifies multiple targets that may inform therapeutic strategies for patients with PDAC.
Authors
- Dennis Gong (ORCID: https://orcid.org/0000-0002-1892-8312)
- Kevin S. Kapner (ORCID: https://orcid.org/0000-0002-2306-2373)
- Carina Shiau (ORCID: https://orcid.org/0000-0002-4164-1360)
- Julien Dilly (ORCID: https://orcid.org/0000-0002-4006-5285)
- Seema Chugh (ORCID: https://orcid.org/0000-0003-1486-0725)
- Harshabad Singh (ORCID: https://orcid.org/0000-0001-6295-2013)
- William L. Hwang (ORCID: https://orcid.org/0000-0003-4514-8837)
- Francisca Vázquez (ORCID: https://orcid.org/0000-0002-2857-4685)
- Patrick Yu
- Daniel Zhao (ORCID: https://orcid.org/0000-0001-7779-5452)
- Kyle E. Evans (ORCID: https://orcid.org/0000-0002-6246-9520)
- Jimmy A. Guo (ORCID: https://orcid.org/0000-0002-4536-9640)
- Joseph Douglas Mancias (ORCID: https://orcid.org/0000-0002-0692-3717)
- Andrew J. Aguirre (ORCID: https://orcid.org/0000-0002-0701-6203)
- Ananya Jambhale
- Eric L. Smith (ORCID: https://orcid.org/0000-0002-0296-7587)
- Peter Chen (ORCID: https://orcid.org/0000-0002-5330-1718)
- Wenzhuo Wu (ORCID: https://orcid.org/0000-0001-6262-9339)
- Kazuki Takahashi (ORCID: https://orcid.org/0000-0001-5924-1376)
- Steven Wang (ORCID: https://orcid.org/0000-0002-5019-5024)
Institutions
- Broad Institute (US)
- Harvard University (US)
- New York Medical College (US)
- University of Washington (US)
- Dana-Farber Cancer Institute (US)
- Center for Systems Biology (US)
- New York University (US)
- Stanford University (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-08-22
- DOI
- https://doi.org/10.1016/j.celrep.2025.116191
- Citations
- 3
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 3.14