Proteogenomic systems analysis identifies targeted therapy resistance mechanisms in EGFR-mutated lung cancer
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Proteogenomic systems analysis identifies targeted therapy resistance mechanisms in EGFR-mutated lung cancer. / Treue, Denise; Bockmayr, Michael; Stenzinger, Albrecht; Heim, Daniel; Hester, Svenja; Klauschen, Frederick.
In: INT J CANCER, Vol. 144, No. 3, 01.02.2019, p. 545-557.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Proteogenomic systems analysis identifies targeted therapy resistance mechanisms in EGFR-mutated lung cancer
AU - Treue, Denise
AU - Bockmayr, Michael
AU - Stenzinger, Albrecht
AU - Heim, Daniel
AU - Hester, Svenja
AU - Klauschen, Frederick
N1 - This article is protected by copyright. All rights reserved.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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 that targeting 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.
AB - 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 that targeting 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.
KW - Journal Article
U2 - 10.1002/ijc.31845
DO - 10.1002/ijc.31845
M3 - SCORING: Journal article
C2 - 30183078
VL - 144
SP - 545
EP - 557
JO - INT J CANCER
JF - INT J CANCER
SN - 0020-7136
IS - 3
ER -
