Wei Wei1, 2, 3, Young Shik Shin1, 3, Min Xue1, Tomoo Matsutani4, Kenta Masui4, Huijun Yang4, Shiro Ikegami4, Yuchao Gu4, Ken Herrmann3, Dazy Johnson3, Xiangming Ding5, Kiwook Hwang1, Jungwoo Kim1, Jian Zhou5, Yapeng Su1, Xinmin Li5, Bruno Bonetti6, Rajesh Chopra7, C. David James8, Webster K. Cavenee4, Timothy F. Cloughesy9, Paul S. Mischel4,*, James R. Heath1, 3,*, Beatrice Gini4
1 Division of Chemistry and Chemical Engineering, NanoSystems Biology Cancer Center, California Institute of Technology, Pasadena, CA 91125, USA
2 Department of Applied Physics and Materials Science, California Institute of Technology, Pasadena, CA 91125, USA
3 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA
4 Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA
5 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
6 Department of Neurological and Movement Sciences, University of Verona, Verona, 37134, Italy
7 Celgene Corporation, San Diego, CA 92121, USA
8 Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
9 Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA
*Corresponding author : Paul S. Mischel, James R. Heath
W.W., Y.S.S., B.G. contributed equally to this work.
Intratumoral heterogeneity of signaling networks may contribute to targeted cancer therapy resistance, including in the highly lethal brain cancer glioblastoma (GBM). We performed single-cell phosphoproteomics on a patient-derived in vivo GBM model of mTOR kinase inhibitor resistance and coupled it to an analytical approach for detecting changes in signaling coordination. Alterations in the protein signaling coordination were resolved as early as 2.5 days after treatment, anticipating drug resistance long before it was clinically manifest. Combination therapies were identified that resulted in complete and sustained tumor suppression in vivo. This approach may identify actionable alterations in signal coordination that underlie adaptive resistance, which can be suppressed through combination drug therapy, including non-obvious drug combinations.