Integrative genomic identification of therapeutic targets for pancreatic cancer

Jimmy A Guo; Dennis Gong; Kyle Evans; Kazuki Takahashi; Ananya D Jambhale; Carina Shiau; Patrick Yu; Steven Wang; Wenbo W Wu; Seema Chugh; Kevin S Kapner; Julien Dilly; Daniel Zhao; Peter Chen; Eric L Smith; Joseph D Mancias; Francisca Vazquez; Harshabad Singh; William L Hwang; Andrew J Aguirre

doi:10.1016/j.celrep.2025.116191

Integrative genomic identification of therapeutic targets for pancreatic cancer

Cell Rep. 2025 Sep 23;44(9):116191. doi: 10.1016/j.celrep.2025.116191. Epub 2025 Aug 21.

Authors

Jimmy A Guo¹, Dennis Gong², Kyle Evans³, Kazuki Takahashi³, Ananya D Jambhale⁴, Carina Shiau⁵, Patrick Yu⁶, Steven Wang⁷, Wenbo W Wu⁵, Seema Chugh⁸, Kevin S Kapner⁹, Julien Dilly⁸, Daniel Zhao¹⁰, Peter Chen¹¹, Eric L Smith⁹, Joseph D Mancias¹², Francisca Vazquez¹¹, Harshabad Singh⁹, William L Hwang¹³, Andrew J Aguirre¹⁴

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.

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.

MeSH terms

Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
Carcinoma, Pancreatic Ductal* / drug therapy
Carcinoma, Pancreatic Ductal* / genetics
Carcinoma, Pancreatic Ductal* / pathology
Cell Line, Tumor
Epithelial-Mesenchymal Transition / genetics
Gene Expression Regulation, Neoplastic
Genomics* / methods
Humans
Molecular Targeted Therapy
Pancreatic Neoplasms* / drug therapy
Pancreatic Neoplasms* / genetics
Pancreatic Neoplasms* / pathology
Proto-Oncogene Proteins p21(ras) / genetics
Proto-Oncogene Proteins p21(ras) / metabolism

Substances

Biomarkers, Tumor
Proto-Oncogene Proteins p21(ras)

Abstract

MeSH terms

Substances

Grants and funding