Abstract
Treatment of high grade gliomas (HGGs) has remained elusive due to their high heterogeneity and aggressiveness. Surgery followed by radiotherapy represents the mainstay of treatment for HGG. However, the unfavorable location of the tumor that usually limits total resection and the resistance to radiation therapy are the major therapeutic problems. Chemotherapy with DNA alkylating agent temozolomide is also used to treat HGG, despite modest effects on survival. Disregulation of several growth factor receptors (GFRs) were detected in HGG and receptor amplification in glioblastoma has been suggested to be responsible for heterogeneity propagation through clonal evolution. Molecularly targeted agents inhibiting these membrane proteins have demonstrated significant cytotoxicity in several types of cancer cells when tested in preclinical models. Platelet-derived growth factor receptors (PDGFRs) and associated signaling were found to be implicated in gliomagenesis, moreover, HGG commonly display a Platelet-derived growth factor (PDGF) autocrine pathway that is not present in normal brain tissues. We have previously shown that both the susceptibility towards PDGFR and the impact of the PDGFR inactivation on the radiation response were different in different HGG cell lines. Therefore, we decided to extend our investigation, using two other HGG cell lines that express PDGFR at the cell surface. Here, we investigated the effect of PDGFR inhibition alone or in combination with gamma radiation in 11 and 15 HGG cell lines. Our results showed that while targeting the PDGFR represents a good means of treatment in HGG, the combination of receptor inhibition with gamma radiation did not result in any discernable difference compared to the single treatment. The PI3K/PTEN/Akt/mTOR and Ras/Raf/MEK/ERK pathways are the major signaling pathways emerging from the GFRs, including PDGFR. Decreased sensitivity to radiation-induced cell death are often associated with redundancy in these pro-survival signaling pathways. Here we found that Phosphoinositide 3-kinases (PI3K), Extracellular-signal-regulated kinase 1/2 (ERK1/2), or c-Jun N-terminal kinase 1/2 (JNK1/2) inactivation induced radiosensitivity in HGG cells.
Highlights
High grade gliomas (HGGs) are, according to the World Health Organization (WHO), a type of astrocytoma originating from the neuroglial cells of the central nervous system (CNS) [1].In spite of general efforts made for many years to improve the therapies for high grade gliomas (HGGs) patients, their prognosis remains poor
Our results showed that while targeting the Platelet-derived growth factor receptors (PDGFRs) represents a good means of treatment in HGG, the combination of receptor inhibition with gamma radiation did not result in any discernable difference compared to the single treatment
We have previously shown that the HGG cell lines express different PDGFR amounts at the cell surface and exhibit different susceptibility towards PDGFR inhibition [13]
Summary
High grade gliomas (HGGs) are, according to the World Health Organization (WHO), a type of astrocytoma originating from the neuroglial cells of the central nervous system (CNS) [1].In spite of general efforts made for many years to improve the therapies for HGG patients, their prognosis remains poor. High grade gliomas (HGGs) are, according to the World Health Organization (WHO), a type of astrocytoma originating from the neuroglial cells of the central nervous system (CNS) [1]. In the last decades, as a consequence of the advances made in understanding the molecular basis of gliomas, some new agents have been tested. These new therapies include, among others, targeted therapies and immunotherapy [2]. The amplification of PDGF and PDGFR genes is not as common as EGFR, it still is encountered in about 16% of human gliomas [3]
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