Novel p21-Activated Kinase 4 (PAK4) Allosteric Modulators Overcome Drug Resistance and Stemness in Pancreatic Ductal Adenocarcinoma.
Novel p21-Activated Kinase 4 (PAK4) Allosteric Modulators Overcome Drug Resistance and Stemness in Pancreatic Ductal Adenocarcinoma.
复制标题
新型的P21激活激酶4（PAK4）变构调节剂克服胰腺导管腺癌中的耐药性和干性。
DOI：
10.1158/1535-7163.mct-16-0205
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发表时间：
2017-01
影响因子：
5.7
通讯作者：
Azmi AS
中科院分区：
文献类型：
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作者：
Aboukameel A;Muqbil I;Senapedis W;Baloglu E;Landesman Y;Shacham S;Kauffman M;Philip PA;Mohammad RM;Azmi AS
p21活化激酶4 （PAK4）是Rho家族GTPases的关键下游效应物，在胰管腺癌（PDAC）细胞中过度表达，而在正常人胰管上皮（HPDE）细胞中不表达。基因拷贝数扩增研究在PDAC患者队列中证实PAK4扩增使其成为PDAC中一个有吸引力的治疗靶点。我们研究了新型PAK4变构调节剂（PAMs）在PDAC细胞系和化疗耐药流分类PDAC癌症干细胞（CSCs）上的抗肿瘤活性。在多种PDAC小鼠皮下模型中评价了PAMs的毒性和疗效。PAMs （KPT-7523, KPT-7189, KPT-8752， KPT-9307和KPT-9274）在体外对不同的PDAC细胞系显示出抗增殖活性，而不影响正常的HPDE。PDAC细胞生长抑制与诱导凋亡和抑制集落形成同时发生。PAMs抑制PAK4下游的增殖和抗凋亡信号。共免疫沉淀实验显示含有波形蛋白的PAK4复合物被破坏。PAMs通过抑制PAK4破坏CSC球体的形成。此外，PAMs在体外与吉西他滨和奥沙利铂协同作用。KPT-9274目前处于I期临床试验（clinicaltrials.gov; NCT02702492），具有理想的PK特性，并且在小鼠中耐受性良好，每天静脉或口服200mg /kg时没有任何毒性迹象。KPT-9274在PDAC细胞系和CSCs皮下异种移植模型中表现出明显的抗肿瘤活性。这些概念验证研究证明了新型PAK4变构调节剂在PDAC中的抗增殖作用，值得进一步的临床研究。
The p21-activated kinase 4 (PAK4) is a key downstream effector of the Rho family GTPases and is found to be over-expressed in pancreatic ductal adenocarcinoma (PDAC) cells but not in normal human pancreatic ductal epithelia (HPDE). Gene copy number amplification studies in PDAC patient cohorts confirmed PAK4 amplification making it an attractive therapeutic target in PDAC. We investigated the anti-tumor activity of novel PAK4 allosteric modulators (PAMs) on a panel of PDAC cell lines and chemotherapy resistant flow sorted PDAC cancer stem cells (CSCs). The toxicity and efficacy of PAMs were evaluated in multiple sub-cutaneous mouse models of PDAC. PAMs (KPT-7523, KPT-7189, KPT-8752, KPT-9307 and KPT-9274) show anti-proliferative activity in vitro against different PDAC cell lines while sparing normal HPDE. Cell growth inhibition was concurrent with apoptosis induction and suppression of colony formation in PDAC. PAMs inhibited proliferation and anti-apoptotic signals downstream of PAK4. Co-immunoprecipitation experiments showed disruption of PAK4 complexes containing vimentin. PAMs disrupted CSC spheroid formation through suppression of PAK4. Moreover PAMs synergize with gemcitabine and oxaliplatin in vitro. KPT-9274, currently in a Phase I clinical trial (clinicaltrials.gov; NCT02702492), possesses desirable PK properties and is well tolerated in mice with the absence of any signs of toxicity when 200 mg/kg daily is administered either intravenously or orally. KPT-9274 as a single agent showed remarkable anti-tumor activity in sub-cutaneous xenograft models of PDAC cell lines and CSCs. These proof-of-concept studies demonstrated the anti-proliferative effects of novel PAK4 allosteric modulators in PDAC and warrant further clinical investigations.