A potent, proteolysis-resistant inhibitor of kallikrein-related peptidase 6 (KLK6) for cancer therapy, developed by combinatorial engineering

Sananes, Amiram; Cohen, Itay; Shahar, Amit; Hockla, Alexandra; Vita, Elena De; Miller, Aubry K.; Radisky, Evette S.; Papo, Niv

doi:10.1074/jbc.ra117.000871

Cited by 25 publications

(34 citation statements)

References 83 publications

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“…Among them, KLK6, a secreted protein with trypsin-like serine peptidase function, has been implicated in the invasion of ovarian cancer, melanoma, and KRAS-mutant colon cancer cells, and is associated with poor prognosis in multiple human cancers (48,(57)(58)(59)(60). KLK6 has demonstrated enzymatic activity against fibrinogen and collagens I and IV and may represent a targetable vulnerability for treatment of PDAC (61). Future studies will be aimed at investigating the functional role of KLK6 and other KRAS-ON/invasive signature genes in subtype switching and PDAC progression.…”

Section: Discussionmentioning

confidence: 99%

Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past decades. Recently, subtypes of pancreatic cancer with different prognoses have been elaborated; however, the inability to model these subtypes has precluded mechanistic investigation of their origins. Here, we present a xenotransplantation model of PDAC in which neoplasms originate from patient-derived organoids injected directly into murine pancreatic ducts. Our model enables distinction of the two main PDAC subtypes: intraepithelial neoplasms from this model progress in an indolent or invasive manner representing the classical or basal-like subtypes of PDAC, respectively. Parameters that influence PDAC subtype specification in this intraductal model include cell plasticity and hyperactivation of the RAS pathway. Finally, through intratumoral dissection and the direct manipulation of RAS gene dosage, we identify a suite of RAS-regulated secreted and membrane-bound proteins that may represent potential candidates for therapeutic intervention in patients with PDAC. SIGNIFICANCE: Accurate modeling of the molecular subtypes of pancreatic cancer is crucial to facilitate the generation of effective therapies. We report the development of an intraductal organoid transplantation model of pancreatic cancer that models the progressive switching of subtypes, and identify stochastic and RAS-driven mechanisms that determine subtype specification.

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Section: Discussionmentioning

confidence: 99%

Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes

et al. 2020

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“…The reversible inhibitors of the members of kallikrein family have been previously reported [ 38 , 39 , 40 ]. Applicable to our targets, the promising inhibitors of KLK6 [ 41 , 42 ] and KLK7 [ 43 ] have been recently characterized. The pre-clinical testing of selected kallikrein inhibitors should be done to validate their use as investigational drugs in clinical trials, especially because of their demonstrated high complexity of interactions between kallikreins.…”

Section: Discussionmentioning

confidence: 99%

Molecular Pathways Associated with Kallikrein 6 Overexpression in Colorectal Cancer

Pandey

Zhou

Chen

et al. 2021

Genes

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Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide. The high mortality of CRC is related to its ability to metastasize to distant organs. The kallikrein-related peptidase Kallikrein 6 (KLK6) is overexpressed in CRC and contributes to cancer cell invasion and metastasis. The goal of this study was to identify KLK6-associated markers for the CRC prognosis and treatment. Tumor Samples from the CRC patients with significantly elevated KLK6 transcript levels were identified in the RNA-Seq data from Cancer Genome Atlas (TCGA) and their expression profiles were evaluated using Gene Ontology (GO), Phenotype and Reactome enrichment, and protein interaction methods. KLK6-high cases had a distinct spectrum of mutations in titin (TTN), APC, K-RAS, and MUC16 genes. Differentially expressed genes (DEGs) found in the KLK6-overexpressing CRCs were associated with cell signaling, extracellular matrix organization, and cell communication regulatory pathways. The top KLK6-interaction partners were found to be the members of kallikrein family (KLK7, KLK8, KLK10), extracellular matrix associated proteins (keratins, integrins, small proline rich repeat, S100A families) and TGF-β, FOS, and Ser/Thr protein kinase signaling pathways. Expression of selected KLK6-associated genes was validated in a subset of paired normal and tumor CRC patient-derived organoid cultures. The performed analyses identified KLK6 itself and a set of genes, which are co-expressed with KLK6, as potential clinical biomarkers for the management of the CRC disease.

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“…These data were in line with the roles of KLK6 in other cancer types. For example, KLK6 was shown to promote breast cancer cell invasiveness, which could be suppressed by a specifically engineered inhibitor of KLK6 [2122]. Meanwhile, in ovarian and colon cancer cells, KLK6 was found to decrease E-cadherin expression and cell adhesion, thereby promoting tumor invasion and metastasis [1112].…”

Section: Discussionmentioning

confidence: 99%

KLK6 Promotes Growth, Migration, and Invasion of Gastric Cancer Cells

et al. 2018

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PurposeKallikrein (KLK) proteases are hormone-like signaling molecules with critical functions in different cancers. This study investigated the expression of KLK6 in gastric cancer and its potential role in the growth, migration, and invasion of gastric cancer cells.Materials and MethodsIn this study, we compared protein levels of KLK6, vascular endothelial growth factor (VEGF), and matrix metallopeptidase (MMP) 9 in normal gastric epithelial and gastric cancer cell lines by western blot. Fluorescence-activated cell sorting was employed to sort 2 clones of SGC-7901 cells with distinct KLK6 expression, namely, KLK6-high (KLK6high) and KLK6-low (KLK6low), which were then expanded. Lastly, immunohistochemical analysis was performed to investigate KLK6 expression in gastric cancer patients.ResultsThe expression levels of KLK6, VEGF, and MMP 9, were significantly higher in the gastric cancer cell lines SGC-7901, BGC-823, MKN-28, and MGC-803 than in the normal gastric epithelial cell line GES-1. Compared to KLK6low cells, KLK6high cells showed enhanced viability, colony-forming ability, migration, and invasion potential in vitro. Importantly, immunohistochemical analysis of a human gastric cancer tissue cohort revealed that the staining for KLK6, VEGF, and MMP9 was markedly stronger in the cancerous tissues than in the adjacent normal tissues. KLK6 expression also correlated with that of VEGF and MMP9 expression, as well as several key clinicopathological parameters.ConclusionsTogether, these results suggest an important role for KLK6 in human gastric cancer progression.

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A potent, proteolysis-resistant inhibitor of kallikrein-related peptidase 6 (KLK6) for cancer therapy, developed by combinatorial engineering

Cited by 25 publications

References 83 publications

Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes

Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes

Molecular Pathways Associated with Kallikrein 6 Overexpression in Colorectal Cancer

KLK6 Promotes Growth, Migration, and Invasion of Gastric Cancer Cells

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