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Few-shot learning creates predictive models of drug response that translate from high-throughput screens to individual patients

Abstract

Cell-line screens create expansive datasets for learning predictive markers of drug response, but these models do not readily translate to the clinic with its diverse contexts and limited data. In the present study, we apply a recently developed technique, few-shot machine learning, to train a versatile neural network model in cell lines that can be tuned to new contexts using few additional samples. The model quickly adapts when switching among different tissue types and in moving from cell-line models to clinical contexts, including patient-derived tumor cells and patient-derived xenografts. It can also be interpreted to identify the molecular features most important to a drug response, highlighting critical roles for RB1 and SMAD4 in the response to CDK inhibition and RNF8 and CHD4 in the response to ATM inhibition. The few-shot learning framework provides a bridge from the many samples surveyed in high-throughput screens (n-of-many) to the distinctive contexts of individual patients (n-of-one).

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Fig. 1: Study design.
Fig. 2: Transfer of predictive models across tissue types.
Fig. 3: Transfer of cell-line models to PDTC lines.
Fig. 4: Transfer of cell-line models to PDXs.
Fig. 5: Model interpretation to identify predictive markers.
Fig. 6: Model predictions and interpretation for the BRAF inhibitor dabrafenib.

Data availability

The datasets generated during and/or analyzed during the current study are all public data: CCLE: https://depmap.org/portal; CERES-corrected CRISPR gene disruption scores: https://depmap.org/portal; GDSC1000 dataset: https://www.cancerrxgene.org/gdsc1000/GDSC1000_WebResources; PDTC dataset: https://figshare.com/articles/Bruna_et_al_A_biobank_of_breast_cancer_explants_with_preserved_intra-tumor_heterogeneity_to_screen_anticancer_compounds_Cell_2016/2069274; PDX dataset: https://www.nature.com/articles/nm.3954. Other miscellaneous datasets that support the findings of the present study are available at http://github.com/idekerlab/TCRP. Source data are provided with this paper.

Code availability

The software implementation of TCRP, along with all supporting code, is available at http://github.com/idekerlab/TCRP. Other supporting software is available as follows: Scikit-learn v.0.20.2: http://scikit-learn.org/stable/index.html; PyTorch 1.0: http://pytorch.org.

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Acknowledgements

We thank the following for their support for the present study: the National Cancer Institute for grants (nos. U54CA209891 to T.I., R01CA204173 to C.B. and K22CA234406 to J.S.), the National Institute of General Medical Sciences for a grant (no. P41GM103504 to T.I.) and the National Human Genome Research Institute for a grant (no. R01HG009979 to T.I.). R.S. was supported by a research grant from the Israel Science Foundation (grant no. 715/18). J.P. was supported by a grant from the National Science Foundation (grant no. 1652815). L.W. and S.M. were supported by the ZonMw TOP grant COMPUTE CANCER (40-00812-98-16012). J.S. was supported by the Cancer Prevention and Research Institute of Texas (CPRIT RR180035).

Author information

Authors and Affiliations

Authors

Contributions

J.M. and T.I. designed the study and developed the conceptual ideas. J.M. and Y.L. implemented the main algorithms. J.M. and S.H.F. collected all the input sources. J.M., S.M., L.F.A.W. and M.H. developed the strategy for alignment of in vitro and in vivo drug responses. J.M., C.J.B. and T.I. interpreted the results. J.M., S.H.F., R.S., C.J.B., J.P., J.P.S. and T.I. wrote the manuscript.

Corresponding author

Correspondence to Trey Ideker.

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Competing interests

T.I. is co-founder of Data4Cure, Inc., is on the Scientific Advisory Board and has an equity interest. T.I. is on the Scientific Advisory Board of Ideaya BioSciences, Inc. and has an equity interest. The terms of these arrangements have been reviewed and approved by the University of California San Diego in accordance with its conflict-of-interest policies. L.W. received project funding from Genmab BV. The other authors declare no competing interests.

Additional information

Peer review information Nature Cancer thanks Cyril Benes, Roland Eils and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Analysis of fitness versus predictive performance for the panel of gene knockouts in our study.

a, Distribution of relative growth values after CRISPR gene knockout, median for all n = 341 cell lines. Blue: pooling knockouts of all n = 17670 genes; Pink: pooling n = 469 knockouts of genes selected in our study. Fitness is corrected by the Copy Number Variation by the CERES algorithm. b, For each knockout of a selected gene, predictive performance (y axis) is computed as the Pearson correlation between predicted and actual growth measurements over all n = 341 cell lines. This performance is displayed as a function of the median growth fitness of that knockout (x axis). Growth fitness is binned according to percentiles, for example the first bin (0-10%) represents the top 10% of selected genes with the strongest median effects on growth. The distribution of predictive performance for each bin is shown with a violin plot. Error bars represent 95% confidence interval.

Source data

Extended Data Fig. 2

Training accuracy of TCRP and other baseline models for all challenges.

Source data

Extended Data Fig. 3 Alternative calculation of model performance using Spearman correlation.

While Pearson correlation is used to calculate model performance in the main text, this supplemental figure provides equivalent performance calculations using the non-parametric rank-based Spearman correlation. a, Related to Fig. 3b on n = 83 PDTC models. b, Related to Fig. 4a on n = 228 PDX models.

Source data

Extended Data Fig. 4 Comparison of transferability of different machine learning models to patient-derived xenografts.

Predictive models were pre-trained using responses of cancer cell lines to perturbations with drugs, one model per drug. Few-shot learning was then performed on 0-10 PDX breast tumor samples exposed to that drug (x-axis), and model accuracy (y-axis) was measured by a, Pearson correlation or b, Spearman correlation on the remaining held-out PDX samples. Results averaged across five drugs (see main text). This experiment considers n = 228 PDX models.

Source data

Extended Data Fig. 5 Interpreting the TCRP model with the framework of Local Interpretable Model-Agnostic Explanations (LIME).

See Methods.

Supplementary information

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Ma, J., Fong, S.H., Luo, Y. et al. Few-shot learning creates predictive models of drug response that translate from high-throughput screens to individual patients. Nat Cancer 2, 233–244 (2021). https://doi.org/10.1038/s43018-020-00169-2

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