Kamashev Dmitrii, Shaban Nina, Suntsova Maria, Raevskiy Mikhail, Efimov Victor, Moisseev Aleksey, Sorokin Maxim, Buzdin Anton
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia.
I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia.
Biomedicines. 2022 Aug 8;10(8):1914. doi: 10.3390/biomedicines10081914.
Trastuzumab, a HER2-targeted antibody, is widely used for targeted therapy of HER2-positive breast cancer (BC) patients; yet, not all of them respond to this treatment. We investigated here whether trastuzumab activity on the growth of HER2-overexpressing BT474 cells may interfere with human peripheral blood endogenous factors. Among 33 individual BC patient blood samples supplemented to the media, BT474 sensitivity to trastuzumab varied up to 14 times. In the absence of trastuzumab, human peripheral blood serum samples could inhibit growth of BT474, and this effect varied ~10 times for 50 individual samples. In turn, the epidermal growth factor (EGF) suppressed the trastuzumab effect on BT474 cell growth. Trastuzumab treatment increased the proportion of BT474 cells in the G0/G1 phases of cell cycle, while simultaneous addition of EGF decreased it, yet not to the control level. We used RNA sequencing profiling of gene expression to elucidate the molecular mechanisms involved in EGF- and human-sera-mediated attenuation of the trastuzumab effect on BT474 cell growth. Bioinformatic analysis of the molecular profiles suggested that trastuzumab acts similarly to the inhibition of PI3K/Akt/mTOR signaling axis, and the mechanism of EGF suppression of trastuzumab activity may be associated with parallel activation of PKC and transcriptional factors ETV1-ETV5.
曲妥珠单抗是一种靶向HER2的抗体，广泛用于HER2阳性乳腺癌（BC）患者的靶向治疗；然而，并非所有患者都对这种治疗有反应。我们在此研究曲妥珠单抗对HER2过表达的BT474细胞生长的活性是否会干扰人外周血内源性因子。在补充到培养基中的33份个体BC患者血样中，BT474对曲妥珠单抗的敏感性差异高达14倍。在没有曲妥珠单抗的情况下，人外周血血清样本可抑制BT474的生长，对于50份个体样本，这种作用的差异约为10倍。反过来，表皮生长因子（EGF）抑制了曲妥珠单抗对BT474细胞生长的作用。曲妥珠单抗处理增加了BT474细胞在细胞周期G0/G1期的比例，而同时添加EGF则降低了该比例，但未降至对照水平。我们使用基因表达的RNA测序分析来阐明参与EGF和人血清介导的对曲妥珠单抗作用于BT474细胞生长的减弱的分子机制。对分子谱的生物信息学分析表明，曲妥珠单抗的作用类似于对PI3K/Akt/mTOR信号轴的抑制，EGF抑制曲妥珠单抗活性的机制可能与PKC和转录因子ETV1 - ETV5的平行激活有关。
