TY - JOUR
T1 - A system-wide approach to monitor responses to synergistic BRAF and EGFR inhibition in colorectal cancer cells
AU - Ressa, Anna
AU - Bosdriesz, Evert
AU - De Ligt, Joep
AU - Mainardi, Sara
AU - Maddalo, Gianluca
AU - Prahallad, Anirudh
AU - Jager, Myrthe
AU - De La Fonteijne, Lisanne
AU - Fitzpatrick, Martin
AU - Groten, Stijn
AU - Altelaar, A.F. Maarten
AU - Bernards, René
AU - Cuppen, Edwin
AU - Wessels, Lodewyk
AU - Heck, Albert J.R.
PY - 2018
Y1 - 2018
N2 - Intrinsic and/or acquired resistance represents one of the great challenges in targeted cancer therapy. A deeper understanding of the molecular biology of cancer has resulted in more efficient strategies, where one or multiple drugs are adopted in novel therapies to tackle resistance. This beneficial effect of using combination treatments has also been observed in colorectal cancer patients harboring the BRAF(V600E) mutation, whereby dual inhibition of BRAF(V600E) and EGFR increases antitumor activity. Notwithstanding this success, it is not clear whether this combination treatment is the only or most effective treatment to block intrinsic resistance to BRAF inhibitors. Here, we investigate molecular responses upon single and multi-target treatments, over time, using BRAF(V600E) mutant colorectal cancer cells as a model system. Through integration of transcriptomic, proteomic and phosphoproteomics data we obtain a comprehensive overview, revealing both known and novel responses. We primarily observe widespread up-regulation of receptor tyrosine kinases and metabolic pathways upon BRAF inhibition. These findings point to mechanisms by which the drug-treated cells switch energy sources and enter a quiescent-like state as a defensive response, while additionally compensating for the MAPK pathway inhibition.
AB - Intrinsic and/or acquired resistance represents one of the great challenges in targeted cancer therapy. A deeper understanding of the molecular biology of cancer has resulted in more efficient strategies, where one or multiple drugs are adopted in novel therapies to tackle resistance. This beneficial effect of using combination treatments has also been observed in colorectal cancer patients harboring the BRAF(V600E) mutation, whereby dual inhibition of BRAF(V600E) and EGFR increases antitumor activity. Notwithstanding this success, it is not clear whether this combination treatment is the only or most effective treatment to block intrinsic resistance to BRAF inhibitors. Here, we investigate molecular responses upon single and multi-target treatments, over time, using BRAF(V600E) mutant colorectal cancer cells as a model system. Through integration of transcriptomic, proteomic and phosphoproteomics data we obtain a comprehensive overview, revealing both known and novel responses. We primarily observe widespread up-regulation of receptor tyrosine kinases and metabolic pathways upon BRAF inhibition. These findings point to mechanisms by which the drug-treated cells switch energy sources and enter a quiescent-like state as a defensive response, while additionally compensating for the MAPK pathway inhibition.
UR - http://www.scopus.com/inward/record.url?scp=85054063415&partnerID=8YFLogxK
U2 - 10.1074/mcp.RA117.000486
DO - 10.1074/mcp.RA117.000486
M3 - Article
C2 - 29970458
AN - SCOPUS:85054063415
SN - 1535-9476
VL - 17
SP - 1892
EP - 1908
JO - Molecular and Cellular Proteomics
JF - Molecular and Cellular Proteomics
IS - 10
ER -