The dismal prognosis of glioblastoma multiforme (GBM) is mainly due to the poor response of GBM patients to any therapeutic modalities, which include ionizing radiation and DNA-alkylating agents. In the last few years, the important role of the DNA damage response (DDR) pathway in tumor formation and modulation of therapeutic response has been appreciated. Interestingly, several of the genetic alterations commonly found in GBMs (such as epidermal growth factor receptor amplification and PTEN inactivation) have also recently been shown to regulate the activity of the DNA repair machinery and, consequently, the response to DNA-damaging agents used routinely in the clinic. In this review, we focus on some of these findings that suggest that at least some of the pathways driving GBM formation could be directly responsible for the therapy resistance of this tumor type. Possible therapeutic approaches exist that may either overcome or take advantage of these GBM genetic alterations to improve the response of these tumors to DNA-damaging therapy. Cancer Res; 71(18); 5945–9. ©2011 AACR.

Glioblastoma multiforme (GBM) is the most frequent cancer of the central nervous system in adults and is among the most aggressive and lethal tumor types. GBM patients routinely undergo maximal tumor mass resection followed by concurrent radiotherapy and chemotherapy, using the alkylating agent temozolomide (TMZ). Despite decades of research efforts, GBM patients remain refractory to current treatment modalities and have a dismal prognosis. Gaining insights into the pathways that determine this poor response to therapy will be instrumental for the development of new therapeutic modalities. Resistance to radiation and chemotherapy characterizes many cancer types; however, it is not clear whether resistance is acquired during tumor progression or if it is intrinsically associated with the genetic events that lead to the tumor formation in the first place. In this review, we highlight some of the recent findings, which suggest that the genetic alterations characterizing GBM genomes might also be responsible for the poor treatment response of this tumor type by directly modulating the activity of the DNA damage response (DDR), namely, the DNA damage checkpoint and the DNA repair machinery. This “DDR-centric” view of glioma biology and response to therapy may provide additional insight into this particularly vexing problem. Currently, several laboratories are exploring the possibility of manipulating the DDR to cause selective tumor cell death through catastrophic genomic instability; therefore, we also focus here on some of the possible therapeutic modalities that could overcome and/or exploit GBM genetic alterations to improve the response to radiotherapy and chemotherapy.

In response to DNA damage, cells activate the phosphoinositide 3-kinase (PI3K)–related kinases (PI3KK) ATM, ATR, and DNA-dependent protein kinase (DNA-PK), which in turn phosphorylate multiple downstream substrates, including the effector kinases Chk1 and Chk2, resulting in cell-cycle checkpoint initiation and/or apoptosis. The activation of DDR signaling also requires several accessory proteins known as checkpoint mediators or adaptors, including 53BP1, BRCA1, and MDC1. Recently, it has been proposed that the DDR acts as a barrier against tumor progression, in which early malignant lesions have to inactivate p53 or other components of the DDR to progress to a more aggressive status.

The genes encoding components of the ATM/Chk2 and the ATR/Chk1 pathways are subjected to frequent copy-number loss in GBM patients (Fig. 1), with heterozygous loss of CHEK2 being the most frequent event (approximately 20%; ref. 1). Somatic cell gene transfer with the RCAS/tv-a system and platelet-derived growth factor (PDGF)–induced glioma generation have been used to show that some of the essential molecules of the DDR, such as ATM, Chk2, and p53, are required for glioma tumor suppression in mice and that loss of any of those genes not only accelerates tumor formation but also leads to a more aggressive phenotype, increasing the frequency of high-grade tumors (GBMs). Moreover, Chk2-null gliomas show defects in both apoptotic response and cell-cycle checkpoints, which prevent an ionizing radiation (IR)–mediated survival benefit observed in control mice. The evidence points to an indispensible role of Chk2 in IR response in gliomas, but it may not necessarily be directly extended to other molecules of the DDR pathway, because of the intricacy of this signaling pathway. Inhibition of the ATM kinase (the upstream Chk2 activator that acts in concert and in parallel with Chk2 in DNA-damage checkpoint modulation) leads to radiosensitization of human glioma cells in vitro (2, 3). Given the vast collection of proteins that are phosphorylated by ATM (more than 700), it is very difficult to define which of its downstream targets mediates the increased sensitivity to IR in cells treated with an ATM inhibitor. However, one likely function of ATM that contributes to this phenotype is its ability to modulate the double-strand break (DSB) repair via homologous recombination (HR; ref. 3). DSBs are the most toxic DNA lesions, and failure to repair them could result in the loss of genetic information and the generation of dangerous genomic rearrangements, which may ultimately lead to cell death. Treatment of the U87 glioma cell line with caffeine or more specific ATM inhibitors (KU-55933 and KU-60019) significantly reduced HR efficiency (2–4) and also affected AKT- and extracellular signal regulated kinase (ERK)–mediated prosurvival signaling and cell migration and/or invasion (2). However, the efficacy of pharmacologic inhibition of ATM in combination with IR remains to be evaluated on GBMs in vivo. Moreover, p53 status is likely to determine the response of such a therapeutic strategy, with p53-functional tumors being resistant and the p53-mutant tumors being sensitive to ATM inhibition (5).

Figure 1.

Multiple signaling pathways altered in GBM tumors modulate the DDR. Genes with copy-number loss and/or inactivating mutations or copy-number gain and/or activating mutations are presented in green or red, respectively. See text for details.

Figure 1.

Multiple signaling pathways altered in GBM tumors modulate the DDR. Genes with copy-number loss and/or inactivating mutations or copy-number gain and/or activating mutations are presented in green or red, respectively. See text for details.

Close modal

The alkylating agent TMZ is administered to GBM patients concurrently with radiotherapy. TMZ leads to the formation of a wide spectrum of methyl adducts typically represented by N-methylpurines, which are rapidly repaired by base excision repair (BER). The cytotoxicity of TMZ is thought to be mediated mainly by the formation of O6-methylguanine (O6-meG) DNA adducts. These methyl groups are normally removed by the methyl guanine methyl transferase (MGMT) enzyme, whereas the unrepaired O6-meGs trigger a futile mismatch repair (MMR) cycle, which eventually leads to DSB formation that induces the activation of both ATM- and ATR-mediated signaling (6). A very prominent effect of TMZ treatment in glioma cells in vitro is a Chk1- and Chk2-dependent G2 to M–cell-cycle arrest (7, 8). It has been shown that Chk2 gene silencing prevents the TMZ-induced G2 arrest (8), whereas ATR gene silencing or pharmacologic inhibition of Chk1 increases TMZ sensitivity (7, 9). The most common mechanism of TMZ resistance in GBM patients is MGMT expression, and MGMT promoter silencing by methylation corresponds to a better therapeutic response to TMZ. A deeper knowledge of the signaling pathways activated by TMZ treatment and how the DNA damage induced by TMZ treatment is repaired will be required to increase its therapeutic efficacy. Inhibition of PARP, a key component of BER, represents an attractive treatment approach in combination with different chemotherapy agents, including TMZ, and it is currently showing promising potential as mono-therapy in HR-deficient tumors (such as BRCA-mutant breast cancer cells). Various PARP inhibitors are in phase I and II clinical trials at the moment, and several of these inhibitors (for example ABT-888, CEP-6800, AG014699, and GP15427) have been successfully used in preclinical mouse xenograft glioma models (10).

The epidermal growth factor receptor (EGFR) is one of the most frequently altered receptor tyrosine kinases (RTK) in GBM patients. It is amplified in approximately 40% of GBM samples overall and in 80% of GBMs of the classical subtype, and the variant III deletion of the extracellular domain (EGFR vIII mutant), the most commonly described event that leads to EGFR activation, is present in about half of these EGFR-amplified tumors. RTK signaling hyperactivation seems to be one of the initial oncogenic events in the majority of GBM, most probably largely mediated through the PI3K/Akt/mTOR and Ras/mitogen-activated protein kinase (MAPK) downstream signaling pathway (11). Various studies have shown that the activation of the PI3K/Akt and Ras/MAPK signaling pathways in cancer cells is significantly associated with radiotherapy resistance, either through the modulation of cell survival signaling or, most importantly for the focus of this review, by direct regulation of the DNA repair machinery.

The initial evidence that indicated a possible role of EGFR in regulation of DNA repair was published more than a decade ago (12), and it showed the direct interaction between EGFR and DNA-PK, one of the key components of the nonhomolgous end-joining (NHEJ) machinery. This initial work was extended in the context of radiation treatment with reports showing that both IR and cisplatin induces the translocation of EGFR into the nucleus, where it interacts with DNA-PK and, consequently, results in increased DNA-PK activity (13). This nuclear import of EGFR was inhibited by preincubation with the C225 monoclonal antibody (cetuximab), with a consequent radiosensitization of both lung (A549) and breast (MDA MB231) cancer cell lines, as measured by clonogenic-forming ability and resolution of γH2AX IR-induced foci (IRIF), a standard marker of DSBs (14). Analogously, cetuximab enhanced in vitro and, more importantly, in vivo radiosensitivity in squamous cell carcinoma (SCC) cells of the head and neck (15, 16). Moreover, EGFR inhibition by gefinitib treatment leads to a synergistic increase in growth inhibition when combined with other DNA-damaging agents (cisplatin and etoposide), rather than IR, in a human breast cancer cell line (MCF-7; ref. 17). When studied in more detail, EGFR signaling seems to positively regulate both HR and NHEJ in U87 glioma cells (18), and treatment with EGF ligand induces a dose-dependent increase in HR and NHEJ, which is reduced to 50% of basal levels in the presence of a specific EGFR inhibitor (AG1478). Similarly, activation of EGFR signaling by the expression of EGFR vIII mutant leads to more rapid resolution of γH2AX IRIF and an increase in DNA repair efficiency, whereas the opposite results are obtained when EGFR is inhibited by the EGFR-CD533 dominant-negative mutant. In sum, the results are consistent with the argument that DSB repair is regulated at multiple levels by growth factor signaling and that modulation of DNA repair by EGFR vIII might contribute to the radioresistance of GBMs that carry this mutation. In further support of this idea, a recent report (19) has shown that EGFR vIII expression in mouse astrocytes and human glioma cells (U87) leads to radioresistance by promoting DNA-PK activation and DSB repair, perhaps as a consequence of hyperactivated PI3K/Akt signaling. Mouse orthotopic tumors expressing EGFR vIII are refractory to radiation therapy, continuing to grow after whole-brain radiation, with little effect on overall survival. In U87 cells expressing EGFR vIII, blocking the receptor with the anti-EGFR monoclonal antibody mab-806 reduces the radioresistance of these glioma cells and leads to a reduction of tumor growth, with a concomitant decrease in the tumor microvascular density (20).

Taken together, the data discussed here suggest that EGFR signaling, either directly through the interaction with the DNA repair machinery or indirectly through the activation of PI3K/Akt and Ras/MAPK signaling pathways (Fig. 1), modulates sensitivity to radiation. Therefore, combining radiotherapy with inhibition of EGFR signaling might achieve a better therapeutic outcome, at least in the subset of glioma patients in which this signaling is activated.

Loss of function of the tumor suppressor gene PTEN, mainly by gene deletion or mutation, is a very frequent genetic aberration in GBM patients (approximately 35%). In addition to the well-established role of PTEN in the modulation of the PI3K/Akt/mTOR signaling pathway by the regulation of the intracellular levels of phosphatidylinositol 3,4,5-trisphosphate, PTEN exerts an essential role in maintaining chromosomal integrity via its ability to regulate centromere stability (in a phosphatase-independent manner), DNA DSB repair (possibly through the regulation of Rad51 expression), and Chk1 localization (21). PTEN regulation of HR results in defects in Rad51 foci formation and DSB repair. Comparing PTEN null cells with their isogenic cell lines has shown that the HR deficiency caused by PTEN loss sensitizes tumor cells to PARP inhibitors both in vitro and in vivo (22, 23). Analogously, PTEN-null astrocytes, as well as human glioma lines, have a compromised HR pathway (because of reduced levels of Rad51 paralogs), which confers sensitivity to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a functional analog of TMZ, and renders them sensitive to the PARP inhibition (24). However, at the same time, PTEN loss strongly activated PI3K signaling and resulted in increased resistance to IR, as assayed by colony survival (24, 25). Therefore, PTEN status per se will not be sufficient to predict therapy response in GBM patients because IR and TMZ are used concomitantly.

The signaling abnormalities that drive the other main GBM subsets include PDGF receptor (PDGFR; in the case of the proneural GBMs) and loss of the Ras negative regulator neurofibromatosis type 1 (NF1) gene (in the case of the mesenchymal GBMs; ref. 11). Although less is known about the connection between these pathways and the DDR, some data link them. The PDGF signaling drives tumor formation in a subset of GBMs (approximately 25%), determined either by genetic alterations (such as gene amplification, intrachromosomal deletion, and activating point mutation) of the PDGFRA gene or by overexpression the PDGF ligand (26). Even though direct modulation (like the one observed for EGFR) of the DNA repair machinery by PDGFR has not been described to date, various reports show that treatment with the PDGFR inhibitor imatinib increases radiation sensitivity in glioma cells in vitro and in glioma xenograft mouse models in vivo (27). As mentioned previously in this review, activation of the Ras/MAPK signaling pathways in cancer cells has been associated with radiotherapy resistance; however, it is still unknown whether NF1 inactivation in GBM patients affects the DNA damage checkpoints and/or DNA repair and, ultimately, the treatment response to DNA-damaging agents.

In this review, we have taken the view that the DDR is a central component in the pathways that lead to glioma formation and progression. This DDR-centric view of the world, although clearly biased toward the role of this pathway in glioma biology, provides an alternative view of the connections between these known drivers of tumor formation and assumed contributors to therapeutic resistance. In so doing, we feel that insight to the system as a whole is provided. We have discussed how some of the genetic alterations that characterize the GBM genome can modulate, positively and/or negatively, the response to a given DNA-damaging agent (such as IR or TMZ), and it seems that a balance between the cell survival signals and an effective DNA repair will determine the ultimate outcome to a specific therapy. The DDR is a very convoluted signaling pathway, composed of several hundred proteins, few of which are altered in GBM patients (ref. 1; M. Squatrito and colleagues, manuscript in preparation). A better understanding of the molecular mechanisms that protect cells from the response to a specific DNA-damaging therapy is required to develop new treatments that could overcome this resistance.

It is important to keep in mind that GBM is a very heterogeneous disease composed of multiple subtypes characterized by distinctive genetic alterations that lead to the activation of different signaling pathways. These subtypes are likely to respond in different ways to a given therapy. As an example, the mesenchymal GBM subclass seems more likely to respond to radiotherapy than to alkylating agents (BCNU or TMZ), whereas classical GBM are more prone to respond to alkylating agents than to radiotherapy (28). In addition, any GBM is composed of multiple cell types that are likely to have a heterogeneous sensitivity to any specific treatment. For instance, GBM stem-like cells have been shown to be more radioresistant because of their ability to repair the radiation-induced DNA damage more effectively (29), although this initial evidence has recently been challenged (30). Moreover, similar to what is seen in SHH-driven medulloblastoma, cells that reside in the so-called perivascular niche of PDGF-induced gliomas (some of which seem to have stem-like characteristics) seem to be more resistant to IR.

The studies discussed in this review suggest that there is a strong link between the pathways involved in the process of gliomagenesis and the tumor's resistance to the DNA-damaging agents routinely used in the clinic (such as IR and TMZ). Given the intricate link between these 2 complex biological pathways, it is not surprising that these tumors are highly resistant to the standard cancer treatments that rely on DNA damage. Moreover, future therapeutic strategies for these tumors will need to take into account the effects of the pathways that drive the tumors on the characteristics that make them inherently resistant to therapy.

No potential conflicts of interest were disclosed.

The authors apologize to all colleagues whose work could not be discussed in this review due to space limitations.

The work of M. Squatrito was supported by a Fondazione Italiana Ricerca Cancro (FIRC) fellowship, an American Brain Tumor Association (ABTA) fellowship in memory of Justin Porter, and a Memorial Sloan-Kettering Brain Tumor Center Grant Award. E.C. Holland is a recipient of a National Brain Tumor Society (NBTS) grant award.

1.
Squatrito
M
,
Brennan
CW
,
Helmy
K
,
Huse
JT
,
Petrini
JH
,
Holland
EC
. 
Loss of ATM/Chk2/p53 pathway components accelerates tumor development and contributes to radiation resistance in gliomas
.
Cancer Cell
2010
;
18
:
619
29
.
2.
Golding
SE
,
Rosenberg
E
,
Valerie
N
,
Hussaini
I
,
Frigerio
M
,
Cockcroft
XF
, et al
Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion
.
Mol Cancer Ther
2009
;
8
:
2894
902
.
3.
Golding
SE
,
Rosenberg
E
,
Khalil
A
,
McEwen
A
,
Holmes
M
,
Neill
S
, et al
Double strand break repair by homologous recombination is regulated by cell cycle-independent signaling via ATM in human glioma cells
.
J Biol Chem
2004
;
279
:
15402
10
.
4.
Golding
SE
,
Rosenberg
E
,
Neill
S
,
Dent
P
,
Povirk
LF
,
Valerie
K
. 
Extracellular signal-related kinase positively regulates ataxia telangiectasia mutated, homologous recombination repair, and the DNA damage response
.
Cancer Res
2007
;
67
:
1046
53
.
5.
Jiang
H
,
Reinhardt
HC
,
Bartkova
J
,
Tommiska
J
,
Blomqvist
C
,
Nevanlinna
H
, et al
The combined status of ATM and p53 link tumor development with therapeutic response
.
Genes Dev
2009
;
23
:
1895
909
.
6.
Caporali
S
,
Falcinelli
S
,
Starace
G
,
Russo
MT
,
Bonmassar
E
,
Jiricny
J
, et al
DNA damage induced by temozolomide signals to both ATM and ATR: role of the mismatch repair system
.
Mol Pharmacol
2004
;
66
:
478
91
.
7.
Hirose
Y
,
Berger
MS
,
Pieper
RO
. 
Abrogation of the Chk1-mediated G(2) checkpoint pathway potentiates temozolomide-induced toxicity in a p53-independent manner in human glioblastoma cells
.
Cancer Res
2001
;
61
:
5843
9
.
8.
Hirose
Y
,
Katayama
M
,
Mirzoeva
OK
,
Berger
MS
,
Pieper
RO
. 
Akt activation suppresses Chk2-mediated, methylating agent-induced G2 arrest and protects from temozolomide-induced mitotic catastrophe and cellular senescence
.
Cancer Res
2005
;
65
:
4861
9
.
9.
Caporali
S
,
Levati
L
,
Starace
G
,
Ragone
G
,
Bonmassar
E
,
Alvino
E
, et al
AKT is activated in an ataxia-telangiectasia and Rad3-related-dependent manner in response to temozolomide and confers protection against drug-induced cell growth inhibition
.
Mol Pharmacol
2008
;
74
:
173
83
.
10.
Powell
C
,
Mikropoulos
C
,
Kaye
SB
,
Nutting
CM
,
Bhide
SA
,
Newbold
K
, et al
Pre-clinical and clinical evaluation of PARP inhibitors as tumour-specific radiosensitisers
.
Cancer Treat Rev
2010
;
36
:
566
75
.
11.
Huse
JT
,
Holland
EC
. 
Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma
.
Nat Rev Cancer
2010
;
10
:
319
31
.
12.
Bandyopadhyay
D
,
Mandal
M
,
Adam
L
,
Mendelsohn
J
,
Kumar
R
. 
Physical interaction between epidermal growth factor receptor and DNA-dependent protein kinase in mammalian cells
.
J Biol Chem
1998
;
273
:
1568
73
.
13.
Dittmann
K
,
Mayer
C
,
Fehrenbacher
B
,
Schaller
M
,
Raju
U
,
Milas
L
, et al
Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase
.
J Biol Chem
2005
;
280
:
31182
9
.
14.
Dittmann
K
,
Mayer
C
,
Rodemann
HP
. 
Inhibition of radiation-induced EGFR nuclear import by C225 (Cetuximab) suppresses DNA-PK activity
.
Radiother Oncol
2005
;
76
:
157
61
.
15.
Huang
SM
,
Bock
JM
,
Harari
PM
. 
Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck
.
Cancer Res
1999
;
59
:
1935
40
.
16.
Huang
SM
,
Harari
PM
. 
Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis
.
Clin Cancer Res
2000
;
6
:
2166
74
.
17.
Friedmann
B
,
Caplin
M
,
Hartley
JA
,
Hochhauser
D
. 
Modulation of DNA repair in vitro after treatment with chemotherapeutic agents by the epidermal growth factor receptor inhibitor gefitinib (ZD1839)
.
Clin Cancer Res
2004
;
10
:
6476
86
.
18.
Golding
SE
,
Morgan
RN
,
Adams
BR
,
Hawkins
AJ
,
Povirk
LF
,
Valerie
K
. 
Pro-survival AKT and ERK signaling from EGFR and mutant EGFRvIII enhances DNA double-strand break repair in human glioma cells
.
Cancer Biol Ther
2009
;
8
:
730
8
.
19.
Mukherjee
B
,
McEllin
B
,
Camacho
CV
,
Tomimatsu
N
,
Sirasanagandala
S
,
Nannepaga
S
, et al
EGFRvIII and DNA double-strand break repair: a molecular mechanism for radioresistance in glioblastoma
.
Cancer Res
2009
;
69
:
4252
9
.
20.
Johns
TG
,
McKay
MJ
,
Cvrljevic
AN
,
Gan
HK
,
Taylor
C
,
Xu
H
, et al
MAb 806 enhances the efficacy of ionizing radiation in glioma xenografts expressing the de2-7 epidermal growth factor receptor
.
Int J Radiat Oncol Biol Phys
2010
;
78
:
572
8
.
21.
Shen
WH
,
Balajee
AS
,
Wang
J
,
Wu
H
,
Eng
C
,
Pandolfi
PP
, et al
Essential role for nuclear PTEN in maintaining chromosomal integrity
.
Cell
2007
;
128
:
157
70
.
22.
Dedes
KJ
,
Wetterskog
D
,
Mendes-Pereira
AM
,
Natrajan
R
,
Lambros
MB
,
Geyer
FC
, et al
PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors
.
Sci Transl Med
2010
;
2
:
53ra75
.
23.
Mendes-Pereira
AM
,
Martin
SA
,
Brough
R
,
McCarthy
A
,
Taylor
JR
,
Kim
JS
, et al
Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors
.
EMBO Mol Med
2009
;
1
:
315
22
.
24.
McEllin
B
,
Camacho
CV
,
Mukherjee
B
,
Hahm
B
,
Tomimatsu
N
,
Bachoo
RM
, et al
PTEN loss compromises homologous recombination repair in astrocytes: implications for glioblastoma therapy with temozolomide or poly(ADP-ribose) polymerase inhibitors
.
Cancer Res
2010
;
70
:
5457
64
.
25.
Kao
GD
,
Jiang
Z
,
Fernandes
AM
,
Gupta
AK
,
Maity
A
. 
Inhibition of phosphatidylinositol-3-OH kinase/Akt signaling impairs DNA repair in glioblastoma cells following ionizing radiation
.
J Biol Chem
2007
;
282
:
21206
12
.
26.
Ozawa
T
,
Brennan
CW
,
Wang
L
,
Squatrito
M
,
Sasayama
T
,
Nakada
M
, et al
PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas
.
Genes Dev
2010
;
24
:
2205
18
.
27.
Geng
L
,
Shinohara
ET
,
Kim
D
,
Tan
J
,
Osusky
K
,
Shyr
Y
, et al
STI571 (Gleevec) improves tumor growth delay and survival in irradiated mouse models of glioblastoma
.
Int J Radiat Oncol Biol Phys
2006
;
64
:
263
71
.
28.
Ducray
F
,
de Reyniès
A
,
Chinot
O
,
Idbaih
A
,
Figarella-Branger
D
,
Colin
C
, et al
An ANOCEF genomic and transcriptomic microarray study of the response to radiotherapy or to alkylating first-line chemotherapy in glioblastoma patients
.
Mol Cancer
2010
;
9
:
234
.
29.
Bao
S
,
Wu
Q
,
McLendon
RE
,
Hao
Y
,
Shi
Q
,
Hjelmeland
AB
, et al
Glioma stem cells promote radioresistance by preferential activation of the DNA damage response
.
Nature
2006
;
444
:
756
60
.
30.
McCord
AM
,
Jamal
M
,
Williams
ES
,
Camphausen
K
,
Tofilon
PJ
. 
CD133+ glioblastoma stem-like cells are radiosensitive with a defective DNA damage response compared with established cell lines
.
Clin Cancer Res
2009
;
15
:
5145
53
.