PUBLICATION
CRISPR-based kinome-screening revealed MINK1 as a druggable player to rewire 5FU-resistance in OSCC through AKT/MDM2/p53 axis
- Authors
- Mohanty, S., Mohapatra, P., Shriwas, O., Ansari, S.A., Priyadarshini, M., Priyadarsini, S., Rath, R., Sultania, M., Das Majumdar, S.K., Swain, R.K., Dash, R.
- ID
- ZDB-PUB-221003-2
- Date
- 2022
- Source
- Oncogene 41(45): 4929-4940 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Cell Line, Tumor
- Cisplatin/pharmacology
- Drug Resistance, Neoplasm/genetics
- Fluorouracil/therapeutic use
- Humans
- Mice
- Mice, Nude
- Neoplasm Recurrence, Local/drug therapy
- Protein Serine-Threonine Kinases/genetics
- Proto-Oncogene Proteins c-akt*/metabolism
- Proto-Oncogene Proteins c-mdm2/genetics
- Proto-Oncogene Proteins c-mdm2/metabolism
- Tumor Suppressor Protein p53*/genetics
- Tumor Suppressor Protein p53*/metabolism
- Zebrafish/metabolism
- PubMed
- 36182968 Full text @ Oncogene
Citation
Mohanty, S., Mohapatra, P., Shriwas, O., Ansari, S.A., Priyadarshini, M., Priyadarsini, S., Rath, R., Sultania, M., Das Majumdar, S.K., Swain, R.K., Dash, R. (2022) CRISPR-based kinome-screening revealed MINK1 as a druggable player to rewire 5FU-resistance in OSCC through AKT/MDM2/p53 axis. Oncogene. 41(45):4929-4940.
Abstract
Cisplatin, 5FU and docetaxel (TPF) are the most common chemotherapy regimen used for advanced OSCC. However, many cancer patients experience relapse, continued tumor growth, and spread due to drug resistance, which leads to treatment failure and metastatic disease. Here, using a CRISPR/Cas9 based kinome knockout screening, Misshapen-like kinase 1 (MINK1) is identified as an important mediator of 5FU resistance in OSCC. Analysis of clinical samples demonstrated significantly higher MINK1 expression in the tumor tissues of chemotherapy non-responders as compared to chemotherapy responders. The nude mice and zebrafish xenograft experiments indicate that knocking out MINK1 restores 5FU mediated cell death in chemoresistant OSCC. An antibody based phosphorylation array screen revealed MINK1 as a negative regulator of p53. Mechanistically, MINK1 modulates AKT phosphorylation at Ser473, which enables p-MDM2 (Ser 166) mediated degradation of p53. We also identified lestaurtinib as a potent inhibitor of MINK1 kinase activity. The patient derived TPF resistant cell based xenograft data suggest that lestaurtinib restores 5FU sensitivity and facilitates a significant reduction of tumor burden. Overall, our study suggests that MINK1 is a major driver of 5FU resistance in OSCC. The novel combination of MINK1 inhibitor lestaurtinib and 5FU needs further clinical investigation in advanced OSCC.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping