Proteogenomic systems analysis identifies targeted therapy resistance mechanisms in EGFR-mutated lung cancer

• Verfasst von: Treue, Denise [VerfasserIn]
• Verfasst von: Stenzinger, Albrecht [VerfasserIn]
• Titel: Proteogenomic systems analysis identifies targeted therapy resistance mechanisms in EGFR-mutated lung cancer
• Verf.angabe: Denise Treue, Michael Bockmayr, Albrecht Stenzinger, Daniel Heim, Svenja Hester, Frederick Klauschen
• Jahr des Originals: 2018
• Umfang: 13 S.
• Fussnoten: First published: 05 September 2018 ; Gesehen am 20.02.2019
• Titel Quelle: Enthalten in: International journal of cancer
• Jahr Quelle: 2019
• Band/Heft Quelle: 144(2019), 3, S. 545-557
• ISSN Quelle: 1097-0215
• DOI: doi:10.1002/ijc.31845
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1587824604

Abstract

Cancer precision medicine largely relies on knowledge about genetic aberrations in tumors and next-generation-sequencing studies have shown a high mutational complexity in many cancers. Although a large number of the observed mutations is believed to be not causally linked with cancer, the functional effects of many rare mutations but also of combinations of driver mutations are often unknown. Here, we perform a systems analysis of a model of EGFR-mutated nonsmall cell lung cancer resistant to targeted therapy that integrates whole exome sequencing, global time-course discovery phosphoproteomics and computational modeling to identify functionally relevant molecular alterations. Our approach allows for a complexity reduction from over 2,000 genetic events potentially involved in mediating resistance to only 44 phosphoproteins and 35 topologically close genetic alterations. We perform single- and combination-drug testing against the predicted phosphoproteins and discovered thattargeting of HSPB1, DBNL and AKT1 showed potent antiproliferative effects overcoming resistance against EGFR-inhibitory therapy. Our approach may therefore be used to complement mutational profiling to identify functionally relevant molecular aberrations and propose combination therapies across cancers.