A Runaway PRH/HHEX-Notch3–Positive Feedback Loop Drives Cholangiocarcinoma and Determines Response to CDK4/6 Inhibition

Kitchen, Philip; Lee, Ka Ying; Clark, Danielle J; Lau, Nikki; Lertsuwan, Jomnarong; Sawasdichai, Anyaporn; Satayavivad, Jutamaad; Oltean, Sebastian; Afford, Simon C.; Gaston, Kevin; Jayaraman, Padma-Sheela

doi:10.1158/0008-5472.can-19-0942

Cited by 15 publications

(10 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This indicates that this combination can reduce progression through G1 phase of the cell cycle. Cyclin D1 is a regulatory subunit of CDK4 and CDK6, which have recently been shown to be required for CCA progression, through a transcriptional activator PTH/HHEX [32]. The results described here suggest that afatinib in combination with gemcitabine could add in additional therapeutic options for CDK4/6 resistant cancers.…”

Section: Cancer Research and Treatment (Crt) 22mentioning

confidence: 65%

Effect of Combining EGFR Tyrosine Kinase Inhibitors and Cytotoxic Agents on Cholangiocarcinoma Cells

et al. 2021

View full text Add to dashboard Cite

The potential of members of the epidermal growth factor receptor (ErbB) family as drug targets in cholangiocarcinoma (CCA) has not been extensively addressed. Although phase III clinical trials showed no survival benefits of erlotinib in patients with advanced CCA, the outcome of the standard-of-care chemotherapy treatment for CCA, gemcitabine/cisplatin, is discouraging so we determined the effect of other ErbB receptor inhibitors alone or in conjunction with chemotherapy in CCA cells. Materials and Methods ErbB receptor expression was determined in CCA patient tissues by immunohistochemistry and digital-droplet polymerase chain reaction, and in primary cells and cell lines by immunoblot. Effects on cell viability and cell cycle distribution of combination therapy using ErbB inhibitors with chemotherapeutic drugs was carried out in CCA cell lines. 3D culture of primary CCA cells was then adopted to evaluate the drug effect in a setting that more closely resembles in vivo cell environments. Results CCA tumors showed higher expression of all ErbB receptors compared with resection margins. Primary and CCA cell lines had variable expression of erbB receptors. CCA cell lines showed decreased cell viability when treated with chemotherapeutic drugs (gemcitabine and 5fluorouracil) but also with ErbB inhibitors, particularly afatinib, and with a combination. Sequential treatment of gemcitabine with afatinib was particularly effective. Co-culture of CCA primary cells with cancer-associated fibroblasts decreased sensitivity to chemotherapies, but sensitized to afatinib. Conclusion CANCER RESEARCH AND TREATMENT (CRT) 4

show abstract

Section: Cancer Research and Treatment (Crt) 22mentioning

confidence: 65%

Effect of Combining EGFR Tyrosine Kinase Inhibitors and Cytotoxic Agents on Cholangiocarcinoma Cells

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The study of the gene pathways regulated by Notch 3 and PRH shows that unlike Notch3, PRH is directly involved in activation of Wnt signaling pathway. Furthermore, new therapeutic strategies will be based on the dependence of specific Notch, Wnt and CDK4/6 inhibitors on the activity of PRH[ 80 ].…”

Section: Crosstalk Between Notch Pathway and Other Signalling Cascadementioning

confidence: 99%

Notch signalling pathway in development of cholangiocarcinoma

Rauff

Malik

Bhatti

et al. 2020

WJGO

View full text Add to dashboard Cite

Cholangiocarcinoma (CCA) comprises of extra-hepatic cholangiocarcinoma and intrahepatic cholangiocarcinoma cancers as a result of inflammation of epithelium cell lining of the bile duct. The incidence rate is increasing dramatically worldwide with highest rates in Eastern and South Asian regions. Major risk factors involve chronic damage and inflammation of bile duct epithelium from primary sclerosing cholangitis, chronic hepatitis virus infection, gallstones and liver fluke infection. Various genetic variants have also been identified and as CCA develops on the background of biliary inflammation, diverse range of molecular mechanisms are involved in its progression. Among these, the Notch signalling pathway acts as a major driver of cholangiocarcinogenesis and its components (receptors, ligands and downstream signalling molecules) represent a promising therapeutic targets. Gamma-Secretase Inhibitors have been recognized in inhibiting the Notch pathway efficiently. A comprehensive knowledge of the molecular pathways activated by the Notch signalling cascade as well as its functional crosstalk with other signalling pathways provide better approach in developing innovative therapies against CCA.

show abstract

“…The increased therapeutic efficiency of palbociclib was also shown in the combination with the pan-mTOR inhibitor, MLN0128, in another study (36). Greater effects of CDK4/6 inhibitors were shown in the combination with the inhibitors of other pro-carcinogenic pathways, namely Wnt/β-catenin and Notch 3 (37). Since the primary effect of palbociclib is to arrest the cell cycle which limits the efficacy of cancer treatments, the combined treatment with MLN0128 which promotes CCA cell apoptosis thus provides a new hope for CCA treatment.…”

Section: Biliary Tract Cancermentioning

confidence: 85%

Cyclin-Dependent Kinase 4/6 Inhibitors: A Potential Breakthrough Therapy for Malignancies of Gastrointestinal Tract

Zeng

Zhou

Khowtanapanich

et al. 2022

In Vivo

View full text Add to dashboard Cite

Cancer is the leading cause of death worldwide for which effective treatments remain limited. This article aimed to critically review and discuss the potential of targeting cell cycle machineries as a vital tool for cancer treatment. Cyclin dependent kinase (CDK) 4/6 inhibitors were originally approved by the United State Food and Drug Administration (US FDA) for advanced-stage breast cancer treatment. The nearly double-prolonged survival time in patients who received CDK4/6 inhibitors are superior to the conventional chemotherapy or endocrine therapy alone and, thus, these medications have been designated a breakthrough therapy by the US FDA. The requirement of CDK4/6 in the progression of cancer cells, but probably dispensable in normal cells, makes CDK4/6 a popular target for cancer treatment. The effects of CDK4/6 inhibitors in cancer may also involve the tumor microenvironment in which the therapeutic effects are synergistically pronounced. These emerging roles, hence, prompt investigations regarding their therapeutic potential in other cancers, including gastrointestinal cancer. Many preclinical and clinical studies of CDK4/6 inhibitors in gastrointestinal cancers are underway and, as a result, several new potentials are gradually reported. Contrariwise, the primary effect of this drug group is arresting the cell cycle rather than inducing cell death. The efficacy of using CDK4/6 inhibitors as a single regimen in clinical practice is then limited. In this article, the effects of CDK4/6 inhibitors on the progression of gastrointestinal cancers, at both preclinical and clinical levels are reviewed. The future directions for research and the possibility of CDK4/6 inhibitors being "breakthrough therapy" for gastrointestinal cancers are also discussed.Cancer is recognized as a leading cause of death worldwide, whereas effective treatments are underway and yet to be developed for malignancies in certain organs (1). Cancer cells possess malignant hallmarks that differentiate them from their normal counterparts in the same tissues (2). The abnormality at the genetic or epigenetic levels results in cellular transformation and gain the ability to compete and invade their surrounding tissues. Limitless replication is one of the cancer hallmarks (2). Cancer cells gain this ability through various molecular mechanisms, e.g., amplification of proliferation-associated genes, autoactivation of growth signaling pathways, and the mutation of cell cycle inhibitor genes (3). Although these mechanisms benefit cancer cells to survive, it could be a double-sided sword for their survival. The requirement of unnatural overexpression of genes or proteins makes cancer cells dependent on those oncogenes and this dependency becomes their Achilles' heel. 1580

show abstract

A Runaway PRH/HHEX-Notch3–Positive Feedback Loop Drives Cholangiocarcinoma and Determines Response to CDK4/6 Inhibition

Abstract: A runaway PRH/HHEX-Notch3 positive feedback loop drives cholangiocarcinoma and determines response to CDK4/6 inhibition.

Cited by 15 publications

References 50 publications

Effect of Combining EGFR Tyrosine Kinase Inhibitors and Cytotoxic Agents on Cholangiocarcinoma Cells

Effect of Combining EGFR Tyrosine Kinase Inhibitors and Cytotoxic Agents on Cholangiocarcinoma Cells

Notch signalling pathway in development of cholangiocarcinoma

Cyclin-Dependent Kinase 4/6 Inhibitors: A Potential Breakthrough Therapy for Malignancies of Gastrointestinal Tract

Contact Info

Product

Resources

About