Expression of sorafenib targets in melanoma patients treated with carboplatin, paclitaxel and sorafenib.
Expression of sorafenib targets in melanoma patients treated with carboplatin, paclitaxel and sorafenib.
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索拉非尼靶标在用卡铂，紫杉醇和索拉非尼治疗的黑色素瘤患者中的表达。
DOI：
10.1158/1078-0432.ccr-08-2280
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发表时间：
2009-02-01
期刊：
影响因子：
--
通讯作者：
Kluger HM
中科院分区：
文献类型：
--
作者：
Jilaveanu L;Zito C;Lee SJ;Nathanson KL;Camp RL;Rimm DL;Flaherty KT;Kluger HM
索拉非尼是一种多靶点激酶抑制剂，可抑制MAPK途径和受体酪氨酸激酶的成员，包括VEGF-R2。索拉非尼、卡铂和紫杉醇（SCP）在黑色素瘤患者中具有抗肿瘤活性，但未发现应答与激活B-RafV 600 E突变之间存在关联。我们评估了索拉非尼靶点在SCP治疗患者标本中的表达，并评估了其与缓解和无进展生存期的相关性。使用自动定量分析（AQUA®），我们定量了46例患者治疗前标本中VEGF-R1、VEGF-R2、VEGF-R3、FGF-R1、PDGF-Rβ、c-Kit、B-Raf、C-Raf、MEK 1和ERK 1/2的表达。此外，我们评估了ERK 1/2表达在429档案黑色素瘤。VEGF-R2表达在完全或部分应答患者中显著较高（P=0.0435），而ERK 1/2在无应答患者中较高（P=0.0417）。高ERK 1/2是生存不良的独立预测因子。高ERK 1/2与存档黑色素瘤队列中生存率降低相关，表明高ERK 1/2表达的肿瘤在生物学上更具侵袭性。所有6例VEGF-R2高和ERK 1/2低的患者均对SCP有反应。VEGF-R2高表达与黑色素瘤对SCP的反应相关，而ERK 1/2高表达与耐药性相关。在一项比较该方案与单独化疗的合作组III期试验中，从SCP治疗的黑色素瘤患者中收集标本的工作正在进行中，有必要确认这些发现。这些标志物可能有助于预测索拉非尼与其他化疗药物联合使用时和其他疾病的反应，从而可能消除不可能反应的患者的不必要治疗。
Sorafenib, a multi-target kinase inhibitor, inhibits members of the MAPK pathway and receptor tyrosine kinases, including VEGF-R2. Sorafenib, carboplatin and paclitaxel (SCP) has anti-tumor activity in melanoma patients, but no association was found between response and activating B-RafV600E mutations. We assessed expression of sorafenib targets in SCP-treated patient specimens and evaluated the association with response and progression free survival. Using Automated QUantitative Analysis (AQUA®), we quantified expression of VEGF-R1, VEGF-R2, VEGF-R3, FGF-R1, PDGF-Rβ, c-Kit, B-Raf, C-Raf, MEK1 and ERK1/2 in pre-treatment specimens from 46 patients. Furthermore, we assessed ERK1/2 expression in 429 archival melanomas. VEGF-R2 expression was significantly higher in patients with a complete or partial response (P=0.0435), whereas ERK1/2 was higher in patients who did not respond (P=0.0417). High ERK1/2 was an independent predictor of poor survival. High ERK1/2 was associated with decreased survival in the archival melanoma cohort, suggesting that high ERK1/2 expressing tumors are biologically more aggressive. All of the six patients with both high VEGF-R2 and low ERK1/2 responded to SCP. High VEGF-R2 expression is associated with response to SCP in melanoma, whereas high ERK1/2 is associated with resistance. Collection of specimens from SCP-treated melanoma patients in a cooperative group phase III trial comparing this regimen to the chemotherapy alone is ongoing, and confirmation of these findings is necessary. These markers might be useful for predicting response to sorafenib when given with other chemotherapies and in other diseases, resulting in possible elimination of unnecessary treatment of patients unlikely to respond.