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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
p53 as a biomarker and potential target in gastrointestinal stromal tumors
Chiao-En Wu1, Chiao-Ping Chen1, Wen-Kuan Huang1
1Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.
Abstract:
KIT and PDGFRA play a major role in the oncogenic process in gastrointestinal stroma tumors (GIST) and small molecules have been employed with great success to target the KIT and PDGFRA pathways in this cancer. However, approximately 10% of patients with GIST are resistant to current targeted drug therapy. There is a need to explore other potential targets. Although p53 alterations frequently occur in most cancers, studies regarding p53 in GIST have been limited. The CDKN2A/MDM2/p53 axis regulates cell cycle progression and DNA damage responses, which in turn control tumor growth. This axis is the major event required for transformation from low- to high-risk GIST. Generally, p53 mutation is infrequent in GIST, but p53 overexpression has been reported to be associated with high-risk GIST and unfavorable prognosis, implying that p53 should play a critical role in GIST. Also, Wee1 regulates the cell cycle and the antitumor activity of Wee1 inhibition was reported to be p53 mutant dependent. In addition, Wee1 was reported to have potential activity in GIST through the regulation of KIT protein and this mechanism may be dependent on p53 status. In this article, we review previous reports regarding the role of p53 in GIST and propose targeting the p53 pathway as a novel additional treatment strategy for GIST.
Insights
Targeting the p53 pathway offers a new treatment strategy for gastrointestinal stromal tumors (GIST), especially for patients resistant to current therapies. This approach addresses the critical role of the CDKN2A/MDM2/p53 axis in GIST progression and prognosis.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Gastrointestinal stromal tumors (GIST) are often driven by KIT and PDGFRA pathways, targeted by current therapies.
- Resistance to targeted therapy affects approximately 10% of GIST patients, necessitating alternative treatment strategies.
- The p53 pathway, crucial in cell cycle regulation and DNA damage response, is implicated in GIST progression, particularly in high-risk cases.
Purpose of the Study:
- To review the existing literature on the role of p53 in GIST.
- To explore the potential of targeting the p53 pathway as a novel therapeutic strategy for GIST.
- To investigate the relationship between p53 status and the efficacy of targeting the Wee1 kinase.
Main Methods:
- Literature review of studies on p53 alterations, CDKN2A/MDM2/p53 axis, and Wee1 kinase in GIST.
- Analysis of the association between p53 overexpression and GIST risk and prognosis.
- Examination of Wee1's role in GIST, including its potential dependence on p53 status.
Main Results:
- While p53 mutations are rare in GIST, p53 overexpression is linked to high-risk GIST and poor outcomes.
- The CDKN2A/MDM2/p53 axis is critical for the transformation of low- to high-risk GIST.
- Wee1 kinase inhibition shows potential in GIST, possibly through KIT regulation and p53-dependent mechanisms.
Conclusions:
- The p53 pathway represents a promising, underexplored target for GIST treatment.
- Targeting the p53 pathway could offer an additional strategy for GIST patients, including those resistant to current therapies.
- Further research into p53-dependent mechanisms, such as Wee1 inhibition, is warranted for GIST treatment development.
