ArticleMolecular cancer therapeutics2017
Novel p21-Activated Kinase 4 (PAK4) Allosteric Modulators Overcome Drug Resistance and Stemness in Pancreatic Ductal Adenocarcinoma.
Article in Molecular cancer therapeutics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02702492 (A Phase 1 Open-Label Study of the Safety, Tolerability and Efficacy of KPT-9274, a Dual Inhibitor of PAK4 and NAMPT, in Patients With Advanced Solid Malignancies or Non-Hodgkin's Lymphoma), which is not on this map. Cited by 57 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase 1 Open-Label Study of the Safety, Tolerability and Efficacy of KPT-9274, a Dual Inhibitor of PAK4 and NAMPT, in Patients With Advanced Solid Malignancies or Non-Hodgkin's Lymphoma
Who cites it
57 citing papers in PubMed, 89 citations in OpenAlex.
- Preclinical Assessment with Clinical Validation of Selinexor with Gemcitabine and Nab-Paclitaxel for the Treatment of Pancreatic Ductal Adenocarcinoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2020Trial
- Structural basis for a p21-activated kinase 4 and nicotinamide phosphoribosyltransferase dual inhibitor.Acta crystallographica. Section D, Structural biology · 2026Article
- Nucleotide Metabolism in Health and Disease.MedComm · 2026Review
- First-in-Human Phase I Study of KPT-9274, a First-in-Class Dual Inhibitor of PAK4 and NAMPT, in Patients with Advanced Solid Malignancies.Targeted oncology · 2026Article
- Nuclear-Cytoplasmic Axis in Cancer: From Protein Mislocalization to Anticancer Drug Resistance.Oncology research · 2026Review
- Targeting KRAS mutations: orchestrating cancer evolution and therapeutic challenges.Signal transduction and targeted therapy · 2025Review
- P21-activated kinase 4: a potent oncogene, molecular mechanisms and opportunities for targeted therapy.Cancer cell international · 2025Review
- The Effects of PAK-Regulated Tumour Vasculature on Gemcitabine Response of Pancreatic Cancer.Cancers · 2025Article
- The Role of the p21-Activated Kinase Family in Tumor Immunity.International journal of molecular sciences · 2025Review
- Design, synthesis and pharmacological evaluation of 1,2,3,4-tetrahydrobenzofuro[2,3-Acta pharmaceutica Sinica. B · 2025Article
- Inhibition of NAMPT by PAK4 Inhibitors.International journal of molecular sciences · 2024Article
- Channeling Nicotinamide Phosphoribosyltransferase (NAMPT) to Address Life and Death.Journal of medicinal chemistry · 2024Review
- Targeting PAK4 reverses cisplatin resistance in NSCLC by modulating ER stress.Cell death discovery · 2024Article
- Anticancer Efficacy of KRASG12C Inhibitors Is Potentiated by PAK4 Inhibitor KPT9274 in Preclinical Models of KRASG12C-Mutant Pancreatic and Lung Cancers.Molecular cancer therapeutics · 2023Article
- PAK4 inhibition significantly potentiates Gemcitabine activity in PDAC cells via inhibition of Wnt/β-catenin, p-ERK/MAPK and p-AKT/PI3K pathways.Biochemistry and biophysics reports · 2023Article
- Targeting NADFrontiers in immunology · 2023Review
- Review
- Review
- Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells.Acta pharmaceutica Sinica. B · 2022Article
- p21-Activated kinases as promising therapeutic targets in hematological malignancies.Leukemia · 2022Review
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.