Wilson George D, Wilson Thomas G, Hanna Alaa, Dabjan Mohamad, Buelow Katie, Torma John, Marples Brian, Galoforo Sandra
Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI, United States.
Department of Radiation Oncology, University of Rochester, Rochester, NY, United States.
Clin Transl Radiat Oncol. 2020 Nov 8;26:15-23. doi: 10.1016/j.ctro.2020.11.003. eCollection 2021 Jan.
There has been little success targeting individual genes in combination with radiation in head and neck cancer. In this study we investigated whether targeting two key pathways simultaneously might be more effective.
We studied the effect of combining dacomitinib (pan-HER, irreversible inhibitor) and gedatolisib (dual PI3K/MTOR inhibitor) with radiation in well characterized, low passage xenograft models of HNSCC in vitro and .
Dacomitinib showed differential growth inhibition in vitro that correlated to EGFR expression whilst gedatolisib was effective in both cell lines. Neither agent radiosensitized the cell lines in vitro. In vivo studies demonstrated that dacomitinib was an effective agent alone and in combination with radiation whilst the addition of gedatolisib did not enhance the effect of these two modalities despite inhibiting phosphorylation of key genes in the PI3K/MTOR pathway.
Our results showed that combining two drugs with radiation provided no added benefit compared to the single most active drug. Dacomitinib deserves more investigation as a radiation sensitizing agent in HNSCC.
在头颈部癌中,将单个基因与放疗联合应用的效果甚微。在本研究中,我们调查了同时靶向两条关键通路是否可能更有效。
我们在体外以及特征明确的低传代头颈部鳞状细胞癌异种移植模型中,研究了达可替尼(泛HER不可逆抑制剂)和吉地替尼(双PI3K/MTOR抑制剂)与放疗联合应用的效果。
达可替尼在体外显示出与表皮生长因子受体(EGFR)表达相关的差异生长抑制作用,而吉地替尼在两种细胞系中均有效。两种药物在体外均未使细胞系产生放射增敏作用。体内研究表明,达可替尼单独使用以及与放疗联合使用均有效,而添加吉地替尼尽管抑制了PI3K/MTOR通路中关键基因的磷酸化,但并未增强这两种治疗方式的效果。
我们的结果表明,与单一最有效的药物相比,两种药物与放疗联合应用并未带来额外益处。达可替尼作为头颈部鳞状细胞癌的放射增敏剂值得进一步研究。