Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease. Overall survival is typically 6 months from diagnosis1. Numerous phase 3 trials of agents effective in other malignancies have failed to benefit unselected PDA populations, although patients do occasionally respond. Studies in other solid tumors have shown that heterogeneity in response is determined, in part, by molecular differences between tumors. Furthermore, treatment outcomes are improved by targeting drugs to tumor subtypes in which they are selectively effective, with breast2 and lung3 cancers providing recent examples. Identification of PDA molecular subtypes has been frustrated by a paucity of tumor specimens available for study. We have overcome this problem by combined analysis of transcriptional profiles of primary PDA samples from several studies, along with human and mouse PDA cell lines. We define three PDA subtypes: classical, quasimesenchymal and exocrine-like, and we present evidence for clinical outcome and therapeutic response differences between them. We further define gene signatures for these subtypes that may have utility in stratifying patients for treatment and present preclinical model systems that may be used to identify new subtype specific therapies.

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Figure 1: Subtypes of PDA in tumors and cell lines and their prognostic significance.
Figure 2: Classical PDA subtype and the GATA6 transcription factor.
Figure 3: Classical subtype cells depend on KRas.
Figure 4: Drug responses differ by subtype.

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Acknowledgements

We are grateful to M. Lenburg and the Gray, Hanahan and Speed labs for discussion. We thank L. Chin (Dana-Farber Cancer Institute) for 3.27, TU8988S, TU8988T, Tu8902, DanG and HupT3, S. Batra (University of Nebraska Medical Center) for Suit2, M. McMahon (UCSF) for HPAC, Capan2, HPAF II, 6.03, CFPac1, MPanc96, 2.13, Panc1, MiaPaca2, 10.05 and Colo357, and A. Singh (Massachusetts General Hospital) for Sw1990. B. Stockwell (New York University) kindly provided pLKOshKRAS 5. R. Adam (Children's Hospital Boston) kindly provided pLKOshGATA6 5. E.A.C. was supported by a Young Investigator Award from the American Society of Clinical Oncology and US National Cancer Institute (NCI) K08 CA137153. A.S. was supported by a US Department of Defense Postdoctoral Fellowship (BC087768). The research in the laboratory of D.H. was supported by an NCI Program Project Grant PO1 CA 117969; D.H. is an American Cancer Society Research Professor. This work was supported by the Director, Office of Science, Office of Biological & Environmental Research, of the United States Department of Energy under contract no. DE-AC02-05CH11231, and by NCI grants P50 CA 58207, P50 CA 83639 and U54 CA 112970 to J.W.G.

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Contributions

E.A.C. and A.S. designed, conducted and interpreted experiments and wrote the manuscript. P.O., W.J.G., M.T., S.G., J.C., J.W., L.J., and H.S.F. performed experiments. K.L.D. and P.T.S. provided support and interpreted experiments. G.E.K. and A.H.K. coordinated clinical sample acquisition. A.B.O. provided statistical expertise. M.A.T. provided support, interpreted experiments and coordinated clinical sample acquisition. D.H. and J.W.G. designed and interpreted experiments, wrote the manuscript and supervised the project.

Corresponding author

Correspondence to Joe W Gray.

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Competing interests

J.C. and K.L.D. are employees of Response Genetics. P.O. is an employee of Pfizer. W.J.G. is an employee of Genomic Health.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Methods (PDF 2739 kb)

Supplementary Table 1

Variable and NMF genes for core clinical PDA microarray data sets (XLS 277 kb)

Supplementary Table 2

Patient identifiers and subtypes for different PDA microarray data sets (XLS 36 kb)

Supplementary Table 3

DWD combined matrix containing samples from UCSF and Badea et al., gene expression microarray datasets and 62 PDA assigner genes (XLS 105 kb)

Supplementary Table 4

Patient characteristics and statistical analysis (XLS 30 kb)

Supplementary Table 5

DWD combined matrix containing score clinical samples and human cell lines gene expression microarray datasets and 62 PDA assigner genes (XLS 110 kb)

Supplementary Table 6

DWD combined matrix containing score clinical samples and mouse cell lines gene expression microarray datasets and 62 PDA assigner genes (XLS 84 kb)

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Collisson, E., Sadanandam, A., Olson, P. et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med 17, 500–503 (2011). https://doi.org/10.1038/nm.2344

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