Abstract | BACKGROUND: METHODS: RESULTS: The combination of Palbociclib and Gedatolisib was superior to the combination of Palbociclib and PD0325901. The combination of Palbociclib and Gedatolisib had synergistic anti-proliferative effects in all cell lines tested [CI range: 0.11-0.69] and resulted in the suppression of S6rp (S240/244), without AKT reactivation. The combination of Palbociclib and Gedatolisib increased BAX and Bcl-2 levels in PIK3CA mutated cell lines. The combination of Palbociclib and Gedatolisib caused MAPK/ERK reactivation, as seen by an increase in expression of total EGFR, regardless of the mutational status of the cells. CONCLUSION: This study shows that the combination of Palbociclib and Gedatolisib has synergistic anti-proliferative effects in both wild-type and mutated CRC cell lines. Separately, the phosphorylation of S6rp may be a promising biomarker of responsiveness to this combination.
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Authors | Cha Len Lee, Mattia Cremona, Angela Farrelly, Julie A Workman, Sean Kennedy, Razia Aslam, Aoife Carr, Stephen Madden, Brian O'Neill, Bryan T Hennessy, Sinead Toomey |
Journal | Cancer biology & therapy
(Cancer Biol Ther)
Vol. 24
Issue 1
Pg. 2223388
(12 31 2023)
ISSN: 1555-8576 [Electronic] United States |
PMID | 37326340
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- mirdametinib
- palbociclib
- Phosphatidylinositol 3-Kinases
- Protein Kinase Inhibitors
- Phosphoinositide-3 Kinase Inhibitors
- Mitogen-Activated Protein Kinase Kinases
- CDK4 protein, human
- Cyclin-Dependent Kinase 4
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Topics |
- Humans
- Phosphatidylinositol 3-Kinases
(metabolism)
- Cell Line, Tumor
- Protein Kinase Inhibitors
(pharmacology, therapeutic use)
- Phosphoinositide-3 Kinase Inhibitors
(pharmacology)
- Colorectal Neoplasms
(drug therapy, genetics, metabolism)
- Mitogen-Activated Protein Kinase Kinases
- Cell Proliferation
- Cyclin-Dependent Kinase 4
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