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  3. Integrative genomic identification of therapeutic targets for pancreatic cancer

Integrative genomic identification of therapeutic targets for pancreatic cancer

  • Cell Rep. 2025 Aug 21;44(9):116191. doi: 10.1016/j.celrep.2025.116191.
Jimmy A Guo 1,  Dennis Gong 2,  Kyle Evans 3,  Kazuki Takahashi 3,  Ananya D Jambhale 4,  Carina Shiau 5,  Patrick Yu 6,  Steven Wang 7,  Wenbo W Wu 5,  Seema Chugh 8,  Kevin S Kapner 9,  Julien Dilly 8,  Daniel Zhao 10,  Peter Chen 11,  Eric L Smith 9,  Joseph D Mancias 12,  Francisca Vazquez 11,  Harshabad Singh 9,  William L Hwang 13,  Andrew J Aguirre 14
Affiliations

Affiliations

  • 1 Broad Institute of MIT and Harvard, Cambridge, MA, USA; School of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 2 Broad Institute of MIT and Harvard, Cambridge, MA, USA; Massachusetts Institute of Technology, Cambridge, MA, USA; Center for Systems Biology, Krantz Family Center for Cancer Research, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.
  • 3 Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
  • 4 Grossman School of Medicine, New York University, New York, NY, USA.
  • 5 Harvard Medical School, Boston, MA, USA.
  • 6 University of Washington, Seattle, WA, USA.
  • 7 Stanford University, Stanford, CA, USA.
  • 8 Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 9 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 10 New York Medical College, Valhalla, NY, USA.
  • 11 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 12 Harvard Medical School, Boston, MA, USA; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 13 Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Systems Biology, Krantz Family Center for Cancer Research, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: whwang1@mgh.harvard.edu.
  • 14 Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: andrew_aguirre@dfci.harvard.edu.
PMID: 40848256 DOI: 10.1016/j.celrep.2025.116191
Abstract

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.

Keywords

CDS2; CP: Cancer; CP: Genomics; biomarkers; cancer dependency map; multi-omics; pancreatic cancer; therapeutic targets.

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