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The regulatory function of mixed lineage kinase 3 in tumor and host immunity
Sandeep Kumar1, Sunil Kumar Singh1, Basabi Rana2
1Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, IL 60612, USA.
Abstract:
Protein kinases are the second most sought-after G-protein coupled receptors as drug targets because of their overexpression, mutations, and dysregulated catalytic activities in various pathological conditions. Till 2019, 48 protein kinase inhibitors have received FDA approval for the treatment of multiple illnesses, of which the majority of them are indicated for different malignancies. One of the attractive sub-group of protein kinases that has attracted attention for drug development is the family members of MAPKs that are recognized to play significant roles in different cancers. Several inhibitors have been developed against various MAPK members; however, none of them as monotherapy has shown sustainable efficacy. One of the MAPK members, called Mixed Lineage Kinase 3 (MLK3), has attracted considerable attention due to its role in inflammation and neurodegenerative diseases; however, its role in cancer is an emerging area that needs more investigation. Recent advances have shown that MLK3 plays a role in cancer cell survival, migration, drug resistance, cell death, and tumor immunity. This review describes how MLK3 regulates different MAPK pathways, cancer cell growth and survival, apoptosis, and host's immunity. We also discuss how MLK3 inhibitors can potentially be used along with immunotherapy for different malignancies.
Insights
Mixed Lineage Kinase 3 (MLK3) is emerging as a key regulator in cancer, influencing cell survival, migration, and immunity. Investigating MLK3 inhibitors alongside immunotherapy may offer new treatment strategies for malignancies.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Protein kinases are crucial drug targets, with many inhibitors approved for malignancies.
- Mitogen-activated protein kinase (MAPK) pathways are implicated in various cancers, but monotherapies lack sustainable efficacy.
- Mixed Lineage Kinase 3 (MLK3), a MAPK member, is increasingly recognized for its roles beyond inflammation and neurodegeneration, particularly in cancer.
Purpose of the Study:
- To review the regulatory roles of MLK3 in cancer cell biology, including survival, migration, drug resistance, apoptosis, and tumor immunity.
- To explore the potential of MLK3 inhibitors as a therapeutic strategy, especially in combination with immunotherapy for various cancers.
Main Methods:
- Literature review focusing on recent advances in MLK3 research.
- Analysis of MLK3's involvement in MAPK signaling pathways.
- Discussion of MLK3's impact on cancer cell phenotypes and host immunity.
Main Results:
- MLK3 regulates critical cancer-related processes such as cell survival, migration, and apoptosis.
- MLK3 influences tumor immunity, presenting a potential target for immunotherapeutic strategies.
- Emerging evidence highlights MLK3's multifaceted role in cancer development and progression.
Conclusions:
- MLK3 is a significant emerging target in oncology.
- Targeting MLK3, potentially in combination with immunotherapy, shows promise for treating diverse malignancies.
- Further investigation into MLK3's role in cancer is warranted to develop novel therapeutic interventions.
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