Local recurrence in head and neck cancer: relationship to radiation resistance and signal transduction.
Local recurrence in head and neck cancer: relationship to radiation resistance and signal transduction.
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发表时间：
2002-03
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通讯作者：
Anjali K. Gupta;W. Mckenna;Charles N. Weber;M. Feldman;J. Goldsmith;R. Mick;M. Machtay;D. Rosenthal
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作者：
Anjali K. Gupta;W. Mckenna;Charles N. Weber;M. Feldman;J. Goldsmith;R. Mick;M. Machtay;D. Rosenthal
局部复发是头颈部恶性肿瘤治疗失败的主要原因。表皮生长因子受体（EGFR）在这种疾病中经常扩增（<或=80%），并可直接或间接通过Ras导致磷脂酰肌醇-3-激酶（PI 3 K）活化。我们以前已经表明，辐射抗性可以通过Ras-PI 3 K途径赋予。在这里，我们调查的贡献，表皮生长因子受体这一途径及其对治疗结果的影响。实验设计在一系列38例H&N癌患者中，通过免疫组织化学染色评估EGFR的过表达。通过对磷酸化Akt（P-Akt）（PI 3 K的下游靶标）染色来评价PI 3 K信号传导。EGFR和P-Akt均与结局相关。在SQ 20 B细胞系（一种来源于复发性喉癌的放射抗性鳞状细胞系）中，在用易瑞沙药理学阻断EGFR、用FTI L744、832药理学阻断Ras或用LY 294002药理学阻断PI 3 K后，测定放射存活率。结果在患者系列中发现P-Akt染色和局部对照之间存在显著相关性。P-Akt染色0-1+的患者的2年局部控制率为100%，而染色2-3+的患者为70.6%（P = 0.04）。在我们的38例H&N癌系列中，30例（78.9%）标本EGFR强阳性（3+），而25例（65.8%）标本P-Akt中度至强阳性（2-3+）。药理学抑制EGFR、Ras和PI 3 K导致SQ 20 B细胞的放射增敏。结论：通过Akt磷酸化评估PI 3 K活化可能是治疗反应的预后标志物，PI 3 K可能是治疗的有用靶点。这些结果还表明，从EGFR到PI 3 K的信号传导可导致辐射抗性。
PURPOSE Locoregional recurrence is the dominant form of treatment failure in head and neck (H&N) cancer. The epidermal growth factor receptor (EGFR) is frequently amplified in this disease (<or=80%) and can lead to activation of phosphatidylinositol-3-kinase (PI3K), both directly and indirectly through Ras. We have shown previously that radioresistance could be conferred via the Ras-PI3K pathway. Here we investigate the contribution of EGFR to this pathway and its impact on treatment outcome. EXPERIMENTAL DESIGN In a series of 38 H&N cancer patients, overexpression of EGFR by immunohistochemical staining was assessed. PI3K signaling was evaluated by staining for phosphorylated Akt (P-Akt), a downstream target of PI3K. Both EGFR and P-Akt were then related to outcome. Radiation survival was determined in the SQ20B cell line, a radioresistant squamous cell line derived from a recurrent laryngeal cancer, after pharmacological blockade of EGFR with Iressa, of Ras by the FTI L744,832, or of PI3K by LY294002. RESULTS A significant association was found between P-Akt staining and local control in the patient series. Two-year local control was 100% for patients staining 0-1+ for P-Akt as compared with 70.6% for patients staining 2-3+ (P = 0.04). In our series of 38 H&N cancers, 30 (78.9%) of the specimens were strongly (3+) positive for EGFR, whereas 25 (65.8%) were moderately to strongly (2-3+) positive for P-Akt. Pharmacologically inhibiting EGFR, Ras, and PI3K led to radiosensitization of SQ20B cells. CONCLUSIONS Evaluation of PI3K activation by Akt phosphorylation might be a prognostic marker for response to therapy, and PI3K could be a useful target for therapy. These results also suggest that signaling from EGFR to PI3K can lead to radioresistance.