Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established 1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses.

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We thank B. Gruenenfelder, M. Lechevalier and D. Thomis for project management; R. Mosher and M. Murakami for their advice on the pathology of PDXs; L. Barys, P. Fordjour, M. Gallagher, B. Gorbatcheva, N. Houde, E. Kurth, J.A. Kwon, Y. Oei, K. O'Malley, D. Rakiec and C. Tauras for their technical support; D. Fox for IT support; S.-M. Maira, C. Fritsch and M. Yao for their helpful discussion; M. Stump, L. Kifule and P. Zhu for support with in vitro proliferation screens; J. Ledell for Chalice software development; and J. Steiger for data interpretation and project management. We received tumor specimens from the US National Disease Research Interchange, the US National Cancer Institute, the Maine Medical Center, the Tufts Medical Center, the Mt Group Inc. and GenenDesign, and we are grateful to the people who consented to donate their tissues to support this work.

Author information

Author notes

    • Mallika Singh
    • , Chao Zhang
    • , Anupama Reddy
    •  & Nancy K Pryer

    Present addresses: Patronus Therapeutics, Inc., San Francisco, California, USA (M.S.); Janssen China R&D and Scientific Affairs, Shanghai, China (C.Z.); BioMarin Pharmaceutical, Inc., Novato, California, USA (N.K.P.); and Duke University, Durham, North Carolina, USA (A.R.).

    • Hui Gao
    • , Joshua M Korn
    •  & Stéphane Ferretti

    These authors contributed equally to this work.

    • Juliet A Williams
    •  & William R Sellers

    These authors jointly directed this work.


  1. Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.

    • Hui Gao
    • , Joshua M Korn
    • , Guizhi Yang
    • , O Alejandro Balbin
    • , Hongbo Cai
    • , Derek Y Chiang
    • , Shawn M Cogan
    • , Scott D Collins
    • , John Green
    • , Colleen Kowal
    • , Rebecca J Leary
    • , Alice Loo
    • , E Robert McDonald III
    • , Jason Merkin
    • , Angad P Singh
    • , Roberto Velazquez
    • , Kavitha Venkatesan
    • , Hans Bitter
    • , Nicholas Keen
    • , Juliet A Williams
    •  & William R Sellers
  2. Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.

    • Stéphane Ferretti
    • , Christian Schnell
    • , Stéphanie Barbe
    • , Ernesta Dammassa
    • , Nicolas Ebel
    • , Audrey Kauffmann
    • , Claudia Röelli
    • , Francesca Santacroce
    • , Walter Tinetto
    • , Sonja Tobler
    • , Fabian Von Arx
    • , Marion Wiesmann
    • , Daniel Wyss
    • , Francesco Hofmann
    • , Robert Cozens
    •  & Michael Rugaard Jensen
  3. Department of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.

    • John E Monahan
    • , Joseph Lehar
    • , Margaret E McLaughlin
    • , Ronald Meyer
    • , Tara L Naylor
    • , Anupama Reddy
    • , David A Ruddy
    •  & Hui Qin Wang
  4. China Novartis Institutes for Biomedical Research, Shanghai, China.

    • Youzhen Wang
    • , Chao Zhang
    • , Yun Zhang
    • , Shannon Chuai
    • , Ying Liang
    • , Zongyao Wang
    • , Fiona Xu
    • , Peter Atadja
    •  & En Li
  5. Oncology Disease Area, Novartis Institutes for Biomedical Research, Emeryville, California, USA.

    • Mallika Singh
    • , Fergal Casey
    • , Susmita Chatterjee
    • , Millicent Embry
    • , Edward Lorenzana
    • , Montesa Patawaran
    • , Fernando Salangsang
    • , Yan Tang
    • , Emma Lees
    •  & Nancy K Pryer


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H.G., S.F., Y.W., M.S., C.Z., C.S., G.Y., S.B., H.C., S. Chatterjee, S.M.C., S.D.C., N.E., M.E., C.K., E. Lorenzana, M.P., C.R., F. Salangsang, F. Santacroce, Y.T., W.T., S.T., R.V., F.V.A., Z.W., D.W. and F.X. performed the PCT trials; H.G., G.Y., Y.Z., S.M.C., J.G., C.K., A.L., R.V., Z.W. and F.X. performed PDX model development; E.D., Y.L., M.E.M. and R.M. performed histopathologic analysis; J.M.K. and E.R.M. led the genomic landscape analysis; J.M.K., F.C., S. Chuai, A.K., J.M., J.L., A.R. and K.V. performed computational biology and bioinformatics analysis; O.A.B., D.Y.C., R.J.L. and A.P.S. performed pan-cancer panel analysis for melanoma resistance; J.E.M., J.G., T.L.N. and D.A.R. performed or directed nuclear acid extraction, quality control and genomic data generation; H.Q.W. performed the PK analysis of the encorafenib and LEE011 combination; M.W. led the in vitro combination screens; H.G., J.M.K., J.M., A.R., O.A.B., D.Y.C. prepared figures and tables for the main text and supplementary information; H.G., J.M.K., J.E.M., S.F., M.S., C.S., O.A.B., A.P.S., D.Y.C., M.W., H.B., J.A.W. and W.R.S. wrote and edited the main text and supplementary information; P.A., R.C., M.R.J., N.K.P., J.A.W., E. Li, E. Lees, F.H., N.K. and W.R.S. contributed to project oversight and advisory roles; J.A.W. and W.R.S. provided overall project leadership.

Competing interests

This research was funded by Novartis, Inc. and all authors were employees thereof at the time the study was performed. The authors declare no other competing financial interests.

Corresponding author

Correspondence to Juliet A Williams.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–13

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    Supplementary Table 1

    Genomic profiling of PDXs and raw response and curve metrics of PCTs.

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