Targeting p21 activated kinase 1 (Pak1) to PAKup Pancreatic Cancer

Jagadeeshan, Sankar; Venkatraman, Ganesh; Rayala, Suresh K.

doi:10.1080/14728222.2016.1239719

Cited by 6 publications

(3 citation statements)

References 21 publications

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“…Activation of PSCs by cancer cells is predominately responsible for fibrosis and stromal remodelling. The role of PAK1 in modulating EMT markers ( e.g ., fibronectin, E-cadherin, and vimentin) has been established in early studies[ 63 ]. A recent study revealed the role of PAK1 in PSC modulation for the first time by showing that inhibition of PAK1 by FRAX597 (a potent group I PAK inhibitor) reduced the activation and proliferation of PSC and increased apoptosis in vitro .…”

Section: Pak Signalling In Pancreatic Cancermentioning

confidence: 99%

p21-activated kinase signalling in pancreatic cancer: New insights into tumour biology and immune modulation

Wang

Baldwin

Nikfarjam

et al. 2018

WJG

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Pancreatic cancer is one of the most aggressive and lethal malignancies worldwide, with a very poor prognosis and a five-year survival rate less than 8%. This dismal outcome is largely due to delayed diagnosis, early distant dissemination and resistance to conventional chemo-therapies. Kras mutation is a well-defined hallmark of pancreatic cancer, with over 95% of cases harbouring Kras mutations that give rise to constitutively active forms of Kras. As important down-stream effectors of Kras, p21-activated kinases (PAKs) are involved in regulating cell proliferation, apoptosis, invasion/migration and chemo-resistance. Immunotherapy is now emerging as a promising treatment modality in the era of personalized anti-cancer therapeutics. In this review, basic knowledge of PAK structure and regulation is briefly summarised and the pivotal role of PAKs in Kras-driven pancreatic cancer is highlighted in terms of tumour biology and chemo-resistance. Finally, the involvement of PAKs in immune modulation in the tumour microenvironment is discussed and the potential advantages of targeting PAKs are explored.

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Section: Pak Signalling In Pancreatic Cancermentioning

confidence: 99%

p21-activated kinase signalling in pancreatic cancer: New insights into tumour biology and immune modulation

Wang

Baldwin

Nikfarjam

et al. 2018

WJG

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“…Since there is a lack of effective therapies and a low survival rate, the research for new biomarkers and therapies targets in PDAC remains active [12][13][14]. There are some gene expression changes in pancreatic cancer already described and presented as biological markers.…”

Section: Introductionmentioning

confidence: 99%

PDAC-ANN: an artificial neural network to predict pancreatic ductal adenocarcinoma based on gene expression

2020

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Background: Although the pancreatic ductal adenocarcinoma (PDAC) presents high mortality and metastatic potential, there is a lack of effective therapies and a low survival rate for this disease. This PDAC scenario urges new strategies for diagnosis, drug targets, and treatment. Methods: We performed a gene expression microarray meta-analysis of the tumor against normal tissues in order to identify differentially expressed genes (DEG) shared among all datasets, named core-genes (CG). We confirmed the CG protein expression in pancreatic tissue through The Human Protein Atlas. It was selected five genes with the highest area under the curve (AUC) among these proteins with expression confirmed in the tumor group to train an artificial neural network (ANN) to classify samples. Results: This microarray included 461 tumor and 187 normal samples. We identified a CG composed of 40 genes, 39 upregulated, and one downregulated. The upregulated CG included proteins and extracellular matrix receptors linked to actin cytoskeleton reorganization. With the Human Protein Atlas, we verified that fourteen genes of the CG are translated, with high or medium expression in most of the pancreatic tumor samples. To train our ANN, we selected the best genes (AHNAK2, KRT19, LAMB3, LAMC2, and S100P) to classify the samples based on AUC using mRNA expression. The network classified tumor samples with an f1-score of 0.83 for the normal samples and 0.88 for the PDAC samples, with an average of 0.86. The PDAC-ANN could classify the test samples with a sensitivity of 87.6 and specificity of 83.1. Conclusion: The gene expression meta-analysis and confirmation of the protein expression allow us to select five genes highly expressed PDAC samples. We could build a python script to classify the samples based on RNA expression. This software can be useful in the PDAC diagnosis.

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“…Moreover, only 10% of human pancreatic cancers are sensitive to gemcitabine (GEM), and the rest is highly resistant to GEM treatment. Interestingly, a major reason for GEM-resistance is GEM-induced abnormal activation of PAK1 (2). Thus, potent PAK1-blockers could effectively overcome their GEM-resistance.…”

Section: Introductionmentioning

confidence: 99%

1,2,3-Triazolyl ester of ketorolac (15K), a potent PAK1 blocker, inhibits both growth and metastasis of orthotopic human pancreatic cancer xenografts in mice

Hennig

Albawardi

Almarzooqi

et al. 2019

DD&T

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More than 90% of human pancreatic cancers carry the oncogenic mutant of Ki-RAS and their growth depends on its downstream kinase PAK1, mainly because PAK1 blocks the apoptosis of cancer cells selectively. We developed a highly cell-permeable PAK1-blocker called 15K from an old painkiller (ketorolac), that is shown here to inhibit the growth of three pancreatic cancer cell lines with IC 50 values ranging 41-88 nM in vitro. The anti-cancer effect of 15K was further investigated in an orthotopic xenograft model with gemcitabine (GEM)-resistant human pancreatic cancer cell lines (AsPC-1 and BxPC-3) expressing luciferase in athymic mice. During 4 weeks, 15K blocks total burden (growth) of both AsPC-1 and BxPC-3 tumors (measured as radians/sec) with the IC 50 below daily dose of 0.1 mg/kg, i.p. In a similar manner 15K reduced both their invasion and metastases as well, while it had no effect on either body weight or hematological parameters even at 5 mg/kg/day. To the best of our knowledge, 15K is so far the most potent among synthetic PAK1-blockers in vivo, and could be potentially useful for therapy of GEM-resistant cancers.

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Targeting p21 activated kinase 1 (Pak1) to PAKup Pancreatic Cancer

Cited by 6 publications

References 21 publications

p21-activated kinase signalling in pancreatic cancer: New insights into tumour biology and immune modulation

p21-activated kinase signalling in pancreatic cancer: New insights into tumour biology and immune modulation

PDAC-ANN: an artificial neural network to predict pancreatic ductal adenocarcinoma based on gene expression

1,2,3-Triazolyl ester of ketorolac (15K), a potent PAK1 blocker, inhibits both growth and metastasis of orthotopic human pancreatic cancer xenografts in mice

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