Organoid profiling identifies common responders to chemotherapy in pancreatic cancer

Hervé Tiriac, Pascal Belleau, Dannielle D. Engle, Dennis Plenker, Astrid Deschênes, Tim D. D. Somerville, Fieke E. M. Froeling, Richard A. Burkhart, Robert E. Denroche, Gun-Ho Jang, Koji Miyabayashi, C. Megan Young, Hardik Patel, Michelle Ma, Joseph F. LaComb, Randze Lerie D. Palmaira, Ammar A. Javed, Jasmine C. Huynh, Molly Johnson, Kanika Arora, Nicolas Robine, Minita Shah, Rashesh Sanghvi, Austin B. Goetz, Cinthya Y. Lowder, Laura Martello, Else Driehuis, Nicolas LeComte, Gokce Askan, Christine A. Iacobuzio-Donahue, Hans Clevers, Laura D. Wood, Ralph H. Hruban, Elizabeth Thompson, Andrew J. Aguirre, Brian M. Wolpin, Aaron Sasson, Joseph Kim, Maoxin Wu, Juan Carlos Bucobo, Peter Allen, Divyesh V. Sejpal, William Nealon, James D. Sullivan, Jordan M. Winter, Phyllis A. Gimotty, Jean L. Grem, Dominick J. DiMaio, Jonathan M. Buscaglia, Paul M. Grandgenett, Jonathan R. Brody, Michael A. Hollingsworth, Grainne M. O'Kane, Faiyaz Notta, Edward Kim, James M. Crawford, Craig Devoe, Allyson Ocean, Christopher L. Wolfgang, Kenneth H. Yu, Ellen Li, Christopher R. Vakoc, Benjamin Hubert, Sandra E. Fischer, Julie M. Wilson, Richard Moffitt, Jennifer Knox, Alexander Krasnitz, Steven Gallinger and David A. Tuveson

Published: 01/09/2018


Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.Significance: New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. Cancer Discov; 8(9); 1112-29. ©2018 AACR.See related commentary by Collisson, p. 1062This article is highlighted in the In This Issue feature, p. 1047.

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