ABSTRACT
BACKGROUND: Studies have demonstrated the efficacy of Palbociclib (CDK 4/6 inhibitor), Gedatolisib (PI3K/mTOR dual inhibitor) and PD0325901 (MEK1/2 inhibitor) in colorectal cancer (CRC), however single agent therapeutics are often limited by the development of resistance. METHODS: We compared the anti-proliferative effects of the combination of Gedatolisib and Palbociclib and Gedatolisib and PD0325901 in five CRC cell lines with varying mutational background and tested their combinations on total and phosphoprotein levels of signaling pathway proteins. 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.
Subject(s)
Colorectal Neoplasms , Phosphatidylinositol 3-Kinases , Humans , Phosphatidylinositol 3-Kinases/metabolism , Cell Line, Tumor , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Mitogen-Activated Protein Kinase Kinases , Cell Proliferation , Cyclin-Dependent Kinase 4ABSTRACT
OBJECTIVE: Researchers often use Neck Disability Index (NDI) scores to classify recovery status in whiplash patients. The purpose of this study was to investigate the optimal cutoff point score for the NDI as a mechanism for differentiating recovery from nonrecovery after whiplash. METHODS: Subjects (N = 123) who had previously sustained whiplash injuries were recruited from 12 clinics. Subjects rated themselves as being recovered (36%) or nonrecovered (64%). This state variable was compared with their NDI score as test variable using the receiver operating characteristic statistic. The area under the receiver operating characteristic curve and optimized cutoff points were computed for the whole group and also dichotomized for sex and age. RESULTS: The mean NDI score for the recovered group was 7.8. It was 27.1 for the nonrecovered group. The cutoff point that optimized sensitivity and specificity for the whole group was an NDI score of 15. For women, it was 19; for older persons, it was 21. CONCLUSION: The optimal NDI score cutoff point for differentiating the recovery state after whiplash is 15. Misclassification errors are likely when using lower values.
