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• W3175258672 abstract "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 resistance. The main purpose of this in vitro study is to comprehensively test two drug combinations [Palbociclib with Gedatolisib (P+G) and Palbociclib with PD0325901 (P+PD)] to determine the most synergistic combination for clinical development. Methods: We compared the anti-proliferative effects of both drug combinations in five CRC cell lines with various mutations (Caco-2, DLD-1, LS1034, SNUC4 and LS411N). Reverse Phase Protein Arrays was used to investigate the effects of P+G on the total and phosphoproteins of the signalling pathways. Results: Our results from toxicology experiments indicated that the P+G is a superior combination. The combination of P+G had synergistic anti-proliferative effects in all cell lines [CI range: 0.11-0.69]. The combination of P+PD is also synergistic in all cell lines [CI range: 0.06-0.44], except LS411N with BRAF V600E mutation [CI=14.7]. The combination of P+G caused significant suppression of S6rp(S240/244) in all cell lines, without AKT reactivation. This indicated efficient blockage of PI3K/AKT/mTOR pathway, even in PIK3CA mutated cell lines. The combination of P+G induced BAX and Bcl-2 levels in PIK3CA mutated cell lines. The combination of P+G caused MAPK/ERK reactivation, as seen in total EGFR increase and this was not mutationally exclusive. Conclusion : This in vitro study demonstrated that the combination of P+G has synergistic anti-proliferative effects in both wild-type and mutated CRC cell lines. This data provides good rationale for further in vivo studies for P+G novel combinative therapy in CRC. Separately, the S6rp(S240/244) may serve a promising biomarker of responsiveness." @default.
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• W3175258672 date "2021-06-23" @default.
• W3175258672 modified "2023-09-25" @default.
• W3175258672 title "Preclinical Drug Testing of the CDK 4/6 Inhibitor Palbociclib in Combination With a PI3K or MEK Inhibitor in Colorectal Cancer Cell Lines" @default.
• W3175258672 doi "https://doi.org/10.21203/rs.3.rs-647758/v1" @default.
• W3175258672 hasPublicationYear "2021" @default.
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