Meme Kanseri Hücrelerinde Pı-103 Inhibitörünün Aktive Reseptör Tirozin Kinaz Ekspresyonuna Etkisinin Incelenmesi

Oncogenic activation of PI3K/Akt/mTOR signaling pathway is frequently seen in breast cancer. Inhibition of signaling pathway by PI3K inhibitors, tyrosine kinase inhibitors and/or monoclonal antibodies causes increase in RTKs expression and activation. In this study, the effects of PI-103 (dual inhibitor of PI3K/mTOR) and AKTi (inhibitor of Akt) and Rapamycin (inhibitor of mTOR) on HER2 and HER3 mRNA expression were investigated in HER2+ SKBR3 breast cancer cells which does not have PTEN and PIK3CA deficiency. AKTi and PI-103 did not cause any significant difference on HER2 and HER3 mRNA expression after 8 and 24 hours of incubation. On the other hand, Rapamycin treatment for 24 hours, changed both HER2 and HER3 mRNA levels significantly (p <0,05). This result points out reactivation inducing effect of rapamycin in these cells. Because, it is shown that Rapamycin increases HER3 protein expression in SKBR3 cells. In our study, time-dependent effects of PI-103 inhibitor on the expression of activated receptor tyrosine kinase (p-HER2 and p-HER3) were also investigated. Dual inhibitor did not change phosphoprotein patern of cells that was observed in control cells. In SKBR3 cells, the finding of unchanged activated RTK levels were in accordance with total protein levels which were not affected from drug treatment. As a result, time-dependent inhibition of PI3K/Akt/mTOR pathway which is the most prominent oncogenic signaling pathway in HER2 overexpressing SKBR3 cells with PI-103 did not trigger HER2 and HER3 expression and reactivation. But, it should be kept in mind that this agent, which can not provide a sustainable signal inhibition, is needed to be combined with other inhibitors for receiving potent antitumoral effect.Meme kanserinde, PI3K/Akt/mTOR sinyal yolağının onkojenik aktivasyonuna sıklıkla rastlanılmaktadır. PI3K inhibitörleri, tirozin kinaz inhibitörleri ve/veya monoklonal antikorlar ile yapılan sinyal yolağı inhibisyonu, RTK ekspresyonlarında ve aktivasyonlarında artışa yol açmaktadır. Bu çalışmada, HER2+, PTEN ve PIK3CA mutasyonu taşımayan SKBR3 insan meme kanseri hücre dizisinde, PI3K/mTOR dual inhibitörü olan PI-103, Akt inhibitörü AKTi ve mTOR inhibitörü Rapamisin'in HER2 ve HER3 mRNA ekspresyon düzeylerine etkisi incelendi. AKTi ve PI-103'ün 8 ve 24 saatlik inkübasyonları sonucunda HER2 ve HER3 mRNA düzeylerinde istatistiksel olarak anlamlı bir fark saptanmadı. Rapamisin ise, 24 saatlik inkübasyon sonucunda, hem HER2 hem de HER3 mRNA ekspresyonunda istatistiksel olarak anlamlı bir artışa sebep oldu (p