Lasri Ayoub, Juric Viktorija, Verreault Maité, Bielle Franck, Idbaih Ahmed, Kel Alexander, Murphy Brona, Sturrock Marc
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York House, Dublin, Ireland.
Inserm U 1127, CNRS UMR 7225, Sorbonne Université, Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
R Soc Open Sci. 2020 Jul 8;7(7):191243. doi: 10.1098/rsos.191243. eCollection 2020 Jul.
Glioblastoma (GBM) is the most aggressive malignant primary brain tumour with a median overall survival of 15 months. To treat GBM, patients currently undergo a surgical resection followed by exposure to radiotherapy and concurrent and adjuvant temozolomide (TMZ) chemotherapy. However, this protocol often leads to treatment failure, with drug resistance being the main reason behind this. To date, many studies highlight the role of O-6-methylguanine-DNA methyltransferase (MGMT) in conferring drug resistance. The mechanism through which MGMT confers resistance is not well studied-particularly in terms of computational models. With only a few reasonable biological assumptions, we were able to show that even a minimal model of MGMT expression could robustly explain TMZ-mediated drug resistance. In particular, we showed that for a wide range of parameter values constrained by novel cell growth and viability assays, a model accounting for only stochastic gene expression of MGMT coupled with cell growth, division, partitioning and death was able to exhibit phenotypic selection of GBM cells expressing MGMT in response to TMZ. Furthermore, we found this selection allowed the cells to pass their acquired phenotypic resistance onto daughter cells in a stable manner (as long as TMZ is provided). This suggests that stochastic gene expression alone is enough to explain the development of chemotherapeutic resistance.
胶质母细胞瘤（GBM）是最具侵袭性的原发性恶性脑肿瘤，患者的中位总生存期为15个月。为了治疗GBM，目前患者要先接受手术切除，然后进行放疗以及同步和辅助替莫唑胺（TMZ）化疗。然而，该方案常常导致治疗失败，耐药性是其背后的主要原因。迄今为止，许多研究都强调了O-6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）在赋予耐药性方面的作用。MGMT产生耐药性的机制尚未得到充分研究，尤其是在计算模型方面。仅通过一些合理的生物学假设，我们就能证明，即使是一个最小化的MGMT表达模型也能有力地解释TMZ介导的耐药性。具体而言，我们表明，对于由新型细胞生长和活力测定法所限定的广泛参数值，一个仅考虑MGMT的随机基因表达以及细胞生长、分裂、分配和死亡的模型，能够展现出表达MGMT的GBM细胞在TMZ作用下的表型选择。此外，我们发现这种选择能使细胞以稳定的方式将其获得的表型耐药性传递给子细胞（只要有TMZ存在）。这表明仅随机基因表达就足以解释化疗耐药性的产生。
