EGFRvIII and DNA Double-Strand Break Repair: A Molecular Mechanism for Radioresistance in Glioblastoma

被引：221

作者：

Mukherjee, Bipasha

McEllin, Brian

Camacho, Cristel V.

Tomimatsu, Nozomi

Sirasanagandala, Shyam ^{[2
,7
,8
]}

Nannepaga, Suraj ^{[3
,7
,8
]}

Hatanpaa, Kimmo J. ^{[4
,7
]}

Mickey, Bruce ^{[5
,7
]}

Madden, Christopher ^{[5
,7
]}

Maher, Elizabeth ^{[2
,3
,7
,8
]}

Boothman, David A. ^{[6
,8
]}

Furnari, Frank ^{[9
]}

Cavenee, Webster K. ^{[9
]}

Bachoo, Robert M. ^{[2
,3
,7
,8
]}

Burma, Sandeep ^{[1
]}

机构：

[1] Univ Texas SW Med Ctr Dallas, Dept Radiat Oncol, Div Mol Radiat Biol, Dallas, TX 75390 USA

[2] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA

[3] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA

[4] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA

[5] Univ Texas SW Med Ctr Dallas, Dept Neurol Surg, Dallas, TX 75390 USA

[6] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA

[7] Univ Texas SW Med Ctr Dallas, Annette G Strauss Ctr Neurooncol, Dallas, TX 75390 USA

[8] Univ Texas SW Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA

[9] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA

来源：

CANCER RESEARCH | 2009年 / 69卷 / 10期

关键词：

GROWTH-FACTOR RECEPTOR; DEPENDENT PROTEIN-KINASE; HUMAN TUMOR-CELLS; CARCINOMA-CELLS; IN-VITRO; INHIBITION; PATHWAY; GLIOMA; RADIOSENSITIZATION; PROLIFERATION;

D O I：

10.1158/0008-5472.CAN-08-4853

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Glioblastoma multiforme (GBM) is the most lethal of brain tumors and is highly resistant to ionizing radiation (IR) and chemotherapy. Here, we report on a molecular mechanism by which a key glioma-specific mutation, epidermal growth factor receptor variant III (EGFRvIII), confers radiation resistance. Using Ink4a/Arf-deficient primary mouse astrocytes, primary astrocytes immortalized by p53/Rb suppression, as well as human U87 glioma cells, we show that EGFRvIII expression enhances clonogenic survival following IR. This enhanced radioresistance is due to accelerated repair of DNA double-strand breaks (DSB), the most lethal lesion inflicted by IR. The EGFR inhibitor gefitinib (Iressa) and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 attenuate the rate of DSB repair. Importantly, expression of constitutively active, myristylated Akt-1 accelerates repair, implicating the PI3K/Akt-1 pathway in radioresistance. Most notably, EGFRvIII-expressing U87 glioma cells show elevated activation of a key DSB repair enzyme, DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Enhanced radioresistance is abrogated by the DNA-PKcs-specific inhibitor NU7026, and EGFRvIII fails to confer radioresistance in DNA-PKes-deficient cells. In vivo, orthotopic U87-EGFRvIII-derived tumors display faster rates of DSB repair following whole-brain radiotherapy compared with U87-derived tumors. Consequently, EGFRvIII-expressing tumors are radioresistant and continue to grow following whole-brain radiotherapy with little effect on overall survival. These in vitro and in vivo data support our hypothesis that EGFRvIII expression promotes DNA-PKcs activation and DSB repair, perhaps as a consequence of hyperactivated PI3K/Akt-1 signaling. Taken together, our results raise the possibility that EGFR and/or DNA-PKcs inhibition concurrent with radiation may be an effective therapeutic strategy for radiosensitizing high-grade gliomas. [Cancer Res 2009:69(10):4252-9]

引用

页码：4252 / 4259

页数：8

共 53 条

[31]

Lammering G, 2001, CLIN CANCER RES, V7, P682

[32] Resistance to tyrosine kinase inhibition by mutant epidermal growth factor receptor variant III contributes to the neoplastic phenotype of glioblastoma multiforme [J].