Novel p21-activated kinase 4 (PAK4) allosteric modulators overcome drug resistance and stemness in pancreatic ductal adenocarcinoma

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][1]), 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. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02702492&atom=%2Fmolcanther%2Fearly%2F2016%2F11%2F15%2F1535-7163.MCT-16-0205.atom