JNCI：PAK1抑制剂能有效治疗BRAF野生型黑色素瘤患者

在携带有BRAF癌基因突变的黑色素瘤患者中，虽然在应用了威罗菲尼或Dabrafenib之后患者对治疗存在显著反应，但是对于野生型BRAF亚型的黑色素瘤患者而言，仍存在大量未满足的临床治疗需要。为了试图探究上述问题，来自Genentech肿瘤转化部门的M. Haverty等进行了相关研究，并将其研究结果发表在JNCI 3月的在线期刊上。
为了探究p21小GTP酶活化激酶1（PAKs）在黑色素瘤患者中所起的作用，研究者确定了在人类黑色素瘤组织中PAK1基因拷贝数和蛋白表达情况。在已知BRAF和RAS（大鼠肉瘤）基因型的黑色素瘤细胞株中，在离体实验或在体实验中应用RNA干扰剂或PF-3758309抑制剂进行治疗可抑制PAK1，这可以帮助我们更好的理解PAK1在黑色素瘤细胞增生和迁移过程中所起的作用。研究者在雌性NCR裸鼠中以在体实验方式评估了肿瘤的发生情况，并且采用三次样条回归和曲线下面积对结果进行分析，所有的统计检验都在双侧进行。
胞浆PAK1蛋白在黑色素瘤中普遍表达（27%），并与BRAF癌基因的激活突变呈负相关，结果具有显著统计学意义。研究者在9%的黑色素瘤患者中观察到了PAK1在11q13局部拷贝数增益（n = 87；拷贝数≥2.5），并且与BRAF基因突变互斥，结果具有显著统计学意义。选择性PAK1抑制可减弱丝裂原活化蛋白激酶（MAPK）的信号传导，以及通过细胞骨架调节途径来介导BRAF野生型黑色素瘤细胞的增生和迁移。采用PF-3758309PAK抑制剂对BRAF野生型黑色素瘤细胞患者进行治疗能减慢SK-MEL23和537MEL移植瘤的生长（抑制程度分别为91%和63%），结果具有显著统计学意义，并且在体实验中，可抑制MAPD旁路的活化。
研究者指出，研究结果证实了PAK1在BRAF野生型黑色素瘤患者中所起的作用，提示对上述患者可采取PAK抑制剂进行治疗。
与黑色素瘤相关的拓展阅读：

• 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
• JAMA：SPECT/CT成像技术有助黑色素瘤前哨淋巴结活检
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P21-Activated Kinase 1 (PAK1) as a Therapeutic Target in BRAF Wild-Type Melanoma
Background
Although remarkable clinical response rates in melanoma have been observed using vemurafenib or dabrafenib in patients with tumors carrying oncogenic mutations in BRAF, a substantial unmet medical need remains for the subset of patients with wild-type BRAF tumors.
Methods
To investigate the role of p21-activated kinases (PAKs) in melanoma, we determined PAK1 genomic copy number and protein expression for a panel of human melanoma tissues. PAK1 was inhibited in vitro and in vivo using RNA interference or PF-3758309 inhibitor treatment in a panel of melanoma cell lines with known BRAF and RAS (rat sarcoma) genotype to better understand its role in melanoma cell proliferation and migration. Tumorigenesis was assessed in vivo in female NCR nude mice and analyzed with cubic spline regression and area under the curve analyses. All statistical tests were two-sided.
Results
Strong cytoplasmic PAK1 protein expression was prevalent in melanomas (27%) and negatively associated with activating mutation of the BRAF oncogene (P < .001). Focal copy number gain of PAK1 at 11q13 was also observed in 9% of melanomas (n = 87; copy number ≥ 2.5) and was mutually exclusive with BRAF mutation (P < .005). Selective PAK1 inhibition attenuated signaling through mitogen-activated protein kinase (MAPK) as well as cytoskeleton-regulating pathways to modulate the proliferation and migration of BRAF wild-type melanoma cells. Treatment of BRAF wild-type melanomas with PF-3758309 PAK inhibitor decreased tumor growth for SK-MEL23 and 537MEL xenografts (91% and 63% inhibition, respectively; P < .001) and MAPK pathway activation in vivo.
Conclusions
Taken together, our results provide evidence for a functional role of PAK1 in BRAF wild-type melanoma and therapeutic use of PAK inhibitors in this indication.