Identifying robust, patient-specific, and predictive biomarkers presents a major obstacle in precision oncology. To optimize patient-specific therapeutic strategies, here we couple pathway knowledge with large-scale drug sensitivity, RNAi, and CRISPR-Cas9 screening data from 460 cell lines. Pathway activity levels are found to be strong predictive biomarkers for the essentiality of 15 proteins, including the essentiality of MAD2L1 in breast cancer patients with high BRCA-pathway activity. We also find strong predictive biomarkers for the sensitivity to 31 compounds, including BCL2 and microtubule inhibitors (MTIs). Lastly, we show that Bcl-xL inhibition can modulate the activity of a predictive biomarker pathway and re-sensitize lung cancer cells and tumors to MTI therapy. Overall, our results support the use of pathways in helping to achieve the goal of precision medicine by uncovering dozens of predictive biomarkers.
Bibliographical noteFunding Information:
We wish to thank Drs. Daniel A. Haber from the Massachusetts General Hospital Cancer Center, William R. Sellers from the Broad Institute of Harvard and MIT, James McFarland from the Broad Institute of Harvard and MIT. R.S. was partially funded by the Fabrikant-Morse Families Research Fund for Humanity, the Moross Integrated Cancer Center, and the Rising Tide Foundation. R.S. is the incumbent of the Roel C. Buck Career Development Chair. G.G. was partially funded by the Paul C. Zamecnik Chair in Oncology, MGH Cancer Center, and by his startup funds at MGH. R.B. was partially funded by the Rothschild Fellowship.
© 2020, The Author(s).