Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Cell Lines, Patient Derived Xenograft Model, Compounds, and Antibodies
2.2. Cell Proliferation/Viability Assay
2.3. PDCD4 Overexpression
2.4. BrdU Incorporation Assay
2.5. Preparation of Whole Cell Extract from Cells and Immunoblot Assays
2.6. Protein Extraction and LC-MS/MS Analysis
2.7. Data Processing and Analysis
2.8. Establishment of GIST Patient Derived Xenografts
2.9. GIST Xenografts and Drug Administration
2.10. Tumor Growth Modeling
3. Results
3.1. IM in Combination with MK-4440 Has Enhanced Viability on In Vitro GIST Cell Growth
3.2. Combination Treatment Increases PDCD4 Expression
3.3. Combination Treatment Causes Cell Cycle Arrest and Increased Cell Death
3.4. Combination Treatment Reduces Tumor Growth In Vivo in IM-Sensitive GIST Only
3.5. MK-4440 in Combination with Ripretinib Increases PDCD4 Expression in GIST Cells
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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GIST-T1 | GIST-T1/829 | |||||
---|---|---|---|---|---|---|
Significantly Downregulated upon Treatment | ||||||
ABCF2 ACACA AGFG1 ARMC9 ATAD2 BMP2K CASP7 CBX1 EIF1 EMC8 | FADS2 FBN1 HMGCS1 HN1 HSBP1 IRF2BP2 KIF11 KPNA2 LSM14B MAGT1 | MKI67 NAV1 ODC1 PFN2 PRKCI PRRC2A RRM2 SEC62 SLC4A1AP SPRY4 | SQLE SQSTM1 TACC3 TAX1BP3 TCAF1 TGFB1I1 TPX2 TYMS ZFYVE16 ZPR1 | ASAH1 ODC1 PTGS2 RAC2 RPL35A SPAG5 TCAF1 | ||
Significantly Upregulated upon Treatment | ||||||
ATP5D BANF1 DERL1 GSTM2 | H1FX HIST1H1C HIST1H4A | MRPL22 NDUFA4 NDUFS4 | PBXIP1 PDCD4 TMEM109 | ATP5D HMGCR ITM2C | NDUFAB1 PDCD4 |
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Kozinova, M.; Joshi, S.; Ye, S.; Belinsky, M.G.; Sharipova, D.; Farma, J.M.; Reddy, S.S.; Litwin, S.; Devarajan, K.; Campos, A.R.; et al. Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor. Cancers 2021, 13, 3699. https://doi.org/10.3390/cancers13153699
Kozinova M, Joshi S, Ye S, Belinsky MG, Sharipova D, Farma JM, Reddy SS, Litwin S, Devarajan K, Campos AR, et al. Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor. Cancers. 2021; 13(15):3699. https://doi.org/10.3390/cancers13153699
Chicago/Turabian StyleKozinova, Marya, Shalina Joshi, Shuai Ye, Martin G. Belinsky, Dinara Sharipova, Jeffrey M. Farma, Sanjay S. Reddy, Samuel Litwin, Karthik Devarajan, Alex Rosa Campos, and et al. 2021. "Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor" Cancers 13, no. 15: 3699. https://doi.org/10.3390/cancers13153699