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
Affiliations
Jimmy A. Guo
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
Dennis Gong
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
Kyle Evans
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
Kazuki Takahashi
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
Ananya D. Jambhale
Grossman School of Medicine, New York University, New York, NY, USA
Carina Shiau
Harvard Medical School, Boston, MA, USA
Patrick Yu
University of Washington, Seattle, WA, USA
Steven Wang
Stanford University, Stanford, CA, USA
Wenbo W. Wu
Harvard Medical School, Boston, MA, USA
Seema Chugh
Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Kevin S. Kapner
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Julien Dilly
Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Daniel Zhao
New York Medical College, Valhalla, NY, USA
Peter Chen
Broad Institute of MIT and Harvard, Cambridge, MA, USA
Eric L. Smith
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Joseph D. Mancias
Harvard Medical School, Boston, MA, USA; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Francisca Vazquez
Broad Institute of MIT and Harvard, Cambridge, MA, USA
Harshabad Singh
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
William L. Hwang
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; Corresponding author
Andrew J. Aguirre
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; Corresponding author
Summary: 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.
