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A tyrosine kinase protein interaction map reveals targetable EGFR network oncogenesis in lung cancer

By Swati Kaushik, Franziska Haderk, Xin Zhao, Hsien-Ming Hu, Khyati N. Shah, Gwendolyn M. Jang, Victor Olivas, Shigeki Nanjo, John Jascur, Vincent B Masto, Daniel Ciznadija, Ido Sloma, Emilie Gross, Scott L Weinrich, Jeffery R Johnson, Trever G. Bivona, Nevan J Krogan, Sourav Bandyopadhyay

Posted 03 Jul 2020
bioRxiv DOI: 10.1101/2020.07.02.185173

Signaling networks balance the activities of many physically interacting proteins and perturbations to this network influence downstream signaling, potentially leading to oncogenic states. Using affinity purification- mass spectrometry we defined this network for all 90 human tyrosine kinases revealing 1,463 mostly novel interactions between these key cancer proteins and diverse molecular complexes. Modulation of interactor levels altered growth phenotypes associated with corresponding tyrosine kinase partners suggesting that tumors may alter the stoichiometries of interactors to maximize oncogenic signaling. We show that the levels of EGFR interactors delineates this form of network oncogenesis in 19% of EGFR wild-type lung cancer patients which were mostly otherwise oncogene negative, predicting sensitivity to EGFR inhibitors in vitro and in vivo. EGFR network oncogenesis occurs through mechanistically distinct network alleles often in cooperation with weak oncogenes in the MAPK pathway. Network oncogenesis may be a common and targetable convergent mechanism of oncogenic pathway activation in cancer. ### Competing Interest Statement S.L.W. is an employee of Pfizer. D.C., I.S., E.M., are employees of Champions oncology. S.B. has received funding from Clovis Oncology, Pfizer, Revolution Medicines and Ideaya Biosciences.

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