Abstract
Simple SummaryGlioblastomas are the deadliest brain tumours. The standard of care associates surgery, radio- and chemotherapy with Temozolomide as the reference drug. Despite this treatment, most of the tumours recur. The characterization of resistance mechanisms is of paramount importance to enable the proposal of more effective therapies. In this work we aimed to evaluate the molecular changes occurring during and after Temozolomide treatment in a glioma cell line. A high plasticity in the integrin repertoire exists in these cells. As an example, variations of the α5β1 integrin expression were observed with a reduction during the treatment and re-expression after removal of the drug. The association of integrin antagonists with p53 reactivators appears to be efficient in recurrent tumours. Specific integrins may thus be particularly targetable at different time points of glioblastoma treatment and combination therapies evaluated according to their time-dependent expression.Despite extensive treatment, glioblastoma inevitably recurs, leading to an overall survival of around 16 months. Understanding why and how tumours resist to radio/chemotherapies is crucial to overcome this unmet oncological challenge. Primary and acquired resistance to Temozolomide (TMZ), the standard-of-care chemotherapeutic drug, have been the subjects of several studies. This work aimed to evaluate molecular and phenotypic changes occurring during and after TMZ treatment in a glioblastoma cell model, the U87MG. These initially TMZ-sensitive cells acquire long-lasting resistance even after removal of the drug. Transcriptomic analysis revealed that profound changes occurred between parental and resistant cells, particularly at the level of the integrin repertoire. Focusing on α5β1 integrin, which we proposed earlier as a glioblastoma therapeutic target, we demonstrated that its expression was decreased in the presence of TMZ but restored after removal of the drug. In this glioblastoma model of recurrence, α5β1 integrin plays an important role in the proliferation and migration of tumoral cells. We also demonstrated that reactivating p53 by MDM2 inhibitors concomitantly with the inhibition of this integrin in recurrent cells may overcome the TMZ resistance. Our results may explain some integrin-based targeted therapy failure as integrin expressions are highly switchable during the time of treatment. We also propose an alternative way to alter the viability of recurrent glioblastoma cells expressing a high level of α5β1 integrin.
Highlights
Glioblastoma (GBM) is the most common and most aggressive malignant brain tumour in adults and is characterized by high proliferation, invasion into normal brain tissue and resistance to therapies [1,2]
We confirmed that the parental cells were sensitive to 50 μM of TMZ and that the U87MG R50 cells were insensitive to TMZ for up to 96 h (Figure 1A)
TMZ resistance was maintained in U87MG R50 OFF cells (Figure 1A)
Summary
Glioblastoma (GBM) is the most common and most aggressive malignant brain tumour in adults and is characterized by high proliferation, invasion into normal brain tissue and resistance to therapies [1,2]. The prognosis of patients with glioblastoma remains poor and has not improved despite numerous clinical trials on new therapeutic propositions [4]. Primary and acquired resistances are the major challenges for the clinical use of standard and targeted therapies in GBM [5,6]. One of the mechanisms of glioblastoma resistance to TMZ involves O6 -methylguanine DNA methyl transferase (MGMT), a suicide enzyme that allows the direct repair of the lesions caused by TMZ, through the removal of a methyl group in position O6 of guanine [7]. Previous studies have shown that intracellular accumulation of the tumour suppressor protein p53 downregulates the expression of MGMT [8,9]
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