A tyrosine kinase protein interaction map reveals targetable EGFR network oncogenesis in lung cancer
Khyati N. Shah,
Gwendolyn M. Jang,
Vincent B Masto,
Scott L Weinrich,
Jeffery R Johnson,
Trever G. Bivona,
Nevan J. Krogan,
Posted 03 Jul 2020
bioRxiv DOI: 10.1101/2020.07.02.185173
Posted 03 Jul 2020
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.
- Downloaded 525 times
- Download rankings, all-time:
- Site-wide: 31,407 out of 94,912
- In cancer biology: 1,011 out of 3,367
- Year to date:
- Site-wide: 5,060 out of 94,912
- Since beginning of last month:
- Site-wide: 582 out of 94,912
Downloads over time
Distribution of downloads per paper, site-wide
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!