JCO：新研究揭示转移性黑色素瘤对威罗菲尼的耐药机制

转移性黑色素瘤对威罗菲尼的耐药机制

在2013年4月8日在线出版的《临床肿瘤学杂志》(Journal of Clinical Oncology)上，发表了美国Vanderbilt-Ingram癌症中心Jeffrey A. Sosman博士等人的一项研究结果，该研究旨在评价BRAF抑制剂威罗菲尼对BRAF^V600突变性黑色素瘤的药效作用及体内获得性耐药机制，以期对威罗菲尼的作用机制进行了解，并最终优化转移性黑色素瘤的治疗方法。

参与NP22657 (BRIM-2)临床II期研究的患者以口服方式接受威罗菲尼治疗(每日两次，每次960 mg)。研究人员针对采集到的系列活检标本进行了免疫组化分析、DNA测序或体细胞突变分析，以实现对促丝裂原活化蛋白激酶(MAPK)信号传导过程中的变化、细胞周期、以及可导致体内或获得性耐药性的因素进行研究。

研究结果表明，威罗菲尼可抑制MAPK信号通路及细胞周期。配对活检结果显示，胞外信号相关激酶(ERK)的磷酸化降低与客观缓解率存在关联(n = 22; P = .013)。磷酸酶与张力蛋白同源基因的低表达量与较低的缓解率间存在轻度关联。研究人员在 92 份标本中发现了MEK1^P124 与BRAF^V600基线变异共存；但这些突变并不能排除客观肿瘤缓解的出现。针对威罗菲尼的获得性耐药与MAPK信号通路的再活化有关，根据观察，进展病变部位ERK1/2磷酸化水平出现升高，且出现了继发性NRAS^Q61突变或MEK1^E203K突变。此前针对出现进展的黑色素瘤所进行的体内试验尚未观察到这两种MEK1突变。

该研究表明，威罗菲尼可抑制肿瘤增殖，并可抑制通过MAPK通路进行的BRAF致癌信号传导。获得性耐药性主要由MAPK再活化所致，这种再活化表现形式为，部分患者的NRAS及MEK1出现继发性突变。此外该研究数据表明，抑制BRAF的下游通路可有助于克服相关药物的获得性耐药性。

与黑色素瘤相关的拓展阅读：

• JNCI：PAK1抑制剂能有效治疗BRAF野生型黑色素瘤患者
• Cancer：阿司匹林可降低黑色素瘤发病风险
• NAT GENET ：肥胖基因或是黑色素瘤的风险因素
• JNCI：HIV阳性者非黑色素瘤皮肤癌发病率高
• JCO:索拉非尼对转移性黑色素瘤无益
• 澳研究出黑色素瘤新疗法 更多信息请点击：有关黑色素瘤更多资讯

Pharmacodynamic Effects and Mechanisms of Resistance to Vemurafenib in Patients With Metastatic Melanoma.
PURPOSE
To assess pharmacodynamic effects and intrinsic and acquired resistance mechanisms of the BRAF inhibitor vemurafenib in BRAFV600-mutant melanoma, leading to an understanding of the mechanism of action of vemurafenib and ultimately to optimization of metastatic melanoma therapy.
METHODS
In the phase II clinical study NP22657 (BRIM-2), patients received oral doses of vemurafenib (960 mg twice per day). Serial biopsies were collected to study changes in mitogen-activated protein kinase (MAPK) signaling, cell-cycle progression, and factors causing intrinsic or acquired resistance by immunohistochemistry, DNA sequencing, or somatic mutation profiling.
Results
Vemurafenib inhibited MAPK signaling and cell-cycle progression. An association between the decrease in extracellular signal-related kinase (ERK) phosphorylation and objective response was observed in paired biopsies (n = 22; P = .013). Low expression of phosphatase and tensin homolog showed a modest association with lower response. Baseline mutations in MEK1P124 coexisting with BRAFV600 were noted in seven of 92 samples; their presence did not preclude objective tumor responses. Acquired resistance to vemurafenib associated with reactivation of MAPK signaling as observed by elevated ERK1/2 phosphorylation levels in progressive lesions and the appearance of secondary NRASQ61 mutations or MEK1Q56P or MEK1E203K mutations. These two activating MEK1 mutations had not previously been observed in vivo in biopsies of progressive melanoma tumors.
CONCLUSION
Vemurafenib inhibits tumor proliferation and oncogenic BRAF signaling through the MAPK pathway. Acquired resistance results primarily from MAPK reactivation driven by the appearance of secondary mutations in NRAS and MEK1 in subsets of patients. The data suggest that inhibition downstream of BRAF should help to overcome acquired resistance.