| Autor: |
Kamashev D; I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia.; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia.; Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia., Shaban N; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia.; Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia., Lebedev T; Engelhardt Institute of Molecular Biology, Moscow 119991, Russia., Prassolov V; Engelhardt Institute of Molecular Biology, Moscow 119991, Russia., Suntsova M; Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia.; World-Class Research Center 'Digital Biodesign and Personalized Healthcare', Sechenov First Moscow State Medical University, Moscow 119991, Russia., Raevskiy M; World-Class Research Center 'Digital Biodesign and Personalized Healthcare', Sechenov First Moscow State Medical University, Moscow 119991, Russia., Gaifullin N; Department of Pathology, Faculty of Medicine, Lomonosov Moscow State University, Moscow 119992, Russia., Sekacheva M; World-Class Research Center 'Digital Biodesign and Personalized Healthcare', Sechenov First Moscow State Medical University, Moscow 119991, Russia., Garazha A; Oncobox Ltd., Moscow 121205, Russia.; Omicsway Corp., Walnut, CA 91789, USA., Poddubskaya E; World-Class Research Center 'Digital Biodesign and Personalized Healthcare', Sechenov First Moscow State Medical University, Moscow 119991, Russia., Sorokin M; I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia.; Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia.; PathoBiology Group, European Organization for Research and Treatment of Cancer (EORTC), 1200 Brussels, Belgium., Buzdin A; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia.; Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia.; World-Class Research Center 'Digital Biodesign and Personalized Healthcare', Sechenov First Moscow State Medical University, Moscow 119991, Russia.; PathoBiology Group, European Organization for Research and Treatment of Cancer (EORTC), 1200 Brussels, Belgium. |
| Abstrakt: |
Regardless of the presence or absence of specific diagnostic mutations, many cancer patients fail to respond to EGFR-targeted therapeutics, and a personalized approach is needed to identify putative (non)responders. We found previously that human peripheral blood and EGF can modulate the activities of EGFR-specific drugs on inhibiting clonogenity in model EGFR-positive A431 squamous carcinoma cells. Here, we report that human serum can dramatically abolish the cell growth rate inhibition by EGFR-specific drugs cetuximab and erlotinib. We show that this phenomenon is linked with derepression of drug-induced G1S cell cycle transition arrest. Furthermore, A431 cell growth inhibition by cetuximab, erlotinib, and EGF correlates with a decreased activity of ERK1/2 proteins. In turn, the EGF- and human serum-mediated rescue of drug-treated A431 cells restores ERK1/2 activity in functional tests. RNA sequencing revealed 1271 and 1566 differentially expressed genes (DEGs) in the presence of cetuximab and erlotinib, respectively. Erlotinib- and cetuximab-specific DEGs significantly overlapped. Interestingly, the expression of 100% and 75% of these DEGs restores to the no-drug level when EGF or a mixed human serum sample, respectively, is added along with cetuximab. In the case of erlotinib, EGF and human serum restore the expression of 39% and 83% of DEGs, respectively. We further assessed differential molecular pathway activation levels and propose that EGF/human serum-mediated A431 resistance to EGFR drugs can be largely explained by reactivation of the MAPK signaling cascade. |
