Aboukameel Amro, Muqbil Irfana, Senapedis William, Baloglu Erkan, Landesman Yosef, Shacham Sharon, Kauffman Michael, Philip Philip A, Mohammad Ramzi M, Azmi Asfar S
Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, Michigan.
Karyopharm Therapeutics, Natick, Massachusetts.
Mol Cancer Ther. 2017 Jan;16(1):76-87. doi: 10.1158/1535-7163.MCT-16-0205. Epub 2016 Nov 15.
The p21-activated kinase 4 (PAK4) is a key downstream effector of the Rho family GTPases and is found to be overexpressed 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 antitumor activity of novel PAK4 allosteric modulators (PAM) on a panel of PDAC cell lines and chemotherapy-resistant flow-sorted PDAC cancer stem cells (CSC). The toxicity and efficacy of PAMs were evaluated in multiple subcutaneous mouse models of PDAC. PAMs (KPT-7523, KPT-7189, KPT-8752, KPT-9307, and KPT-9274) show antiproliferative 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 antiapoptotic 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 pharmacokinetic 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 antitumor activity in subcutaneous xenograft models of PDAC cell lines and CSCs. These proof-of-concept studies demonstrated the antiproliferative effects of novel PAMs in PDAC and warrant further clinical investigations. Mol Cancer Ther; 16(1); 76-87. ©2016 AACR.
p21激活激酶4（PAK4）是Rho家族GTP酶的关键下游效应器，在胰腺导管腺癌（PDAC）细胞中过表达，而在正常人胰腺导管上皮（HPDE）中未过表达。对PDAC患者队列进行的基因拷贝数扩增研究证实了PAK4扩增，使其成为PDAC中有吸引力的治疗靶点。我们研究了新型PAK4变构调节剂（PAM）对一组PDAC细胞系和化疗耐药的流式分选PDAC癌症干细胞（CSC）的抗肿瘤活性。在多个PDAC皮下小鼠模型中评估了PAM的毒性和疗效。PAM（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，同时对正常HPDE细胞无影响。细胞生长抑制与PDAC细胞凋亡诱导和集落形成抑制同时发生。PAM抑制PAK4下游的增殖和抗凋亡信号。免疫共沉淀实验显示含有波形蛋白的PAK4复合物被破坏。PAM通过抑制PAK4破坏CSC球体形成。此外，PAM在体外与吉西他滨和奥沙利铂具有协同作用。目前正在进行I期临床试验（clinicaltrials.gov；NCT02702492）的KPT-9274具有理想的药代动力学特性，当以每日200 mg/kg的剂量静脉内或口服给药时，在小鼠中耐受性良好，没有任何毒性迹象。KPT-9274作为单一药物在PDAC细胞系和CSC的皮下异种移植模型中显示出显著的抗肿瘤活性。这些概念验证研究证明了新型PAM在PDAC中的抗增殖作用，值得进一步的临床研究。《分子癌症治疗》；16(1)；76 - 87。©2016美国癌症研究协会。
