Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer

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.

Cancer Discov. 2018 Sep;8(9):1112-1129. doi: 10.1158/2159-8290.CD-18-0349. Epub 2018 May 31.




Other Contributors

Tiriac H1, Belleau P#1, Engle DD#1, Plenker D1, Deschênes A1, Somerville TDD1, Froeling FEM1, Burkhart RA2, Denroche RE3, Jang GH3, Miyabayashi K1, Young CM1,4, Patel H1, Ma M1, LaComb JF5, Palmaira RLD6, Javed AA2, Huynh JC7, Johnson M8, Arora K8, Robine N8, Shah M8, Sanghvi R8, Goetz AB9, Lowder CY9, Martello L10, Driehuis E11,12, LeComte N6, Askan G6, Iacobuzio-Donahue CA6, Clevers H11,12,13, Wood LD14, Hruban RH14, Thompson E14, Aguirre AJ15, Wolpin BM15, Sasson A16, Kim J16, Wu M17, Bucobo JC5, Allen P6, Sejpal DV18, Nealon W19, Sullivan JD19, Winter JM9, Gimotty PA20, Grem JL21, DiMaio DJ22, Buscaglia JM5, Grandgenett PM23, Brody JR9, Hollingsworth MA23, O’Kane GM24, Notta F3, Kim E7, Crawford JM25, Devoe C26, Ocean A27, Wolfgang CL2, Yu KH6, Li E5, Vakoc CR1, Hubert B8, Fischer SE28,29, Wilson JM3, Moffitt R16,30, Knox J24, Krasnitz A1, Gallinger S31,24,32,33, Tuveson DA34.