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Ref Type Journal Article
PMID (37326340)
Authors Lee CL, Cremona M, Farrelly A, Workman JA, Kennedy S, Aslam R, Carr A, Madden S, O'Neill B, Hennessy BT, Toomey S
Title Preclinical evaluation of the CDK4/6 inhibitor palbociclib in combination with a PI3K or MEK inhibitor in colorectal cancer.
URL
Abstract Text 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.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.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.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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA E545G colorectal adenocarcinoma sensitive Gedatolisib + Palbociclib Preclinical - Cell culture Actionable In a preclinical study, the combination of Ibrance (palbociclib) and Gedatolisib (PF-05212384) synergistically inhibited growth of a colorectal adenocarcinoma cell line harboring PIK3CA E545G in culture (PMID: 37326340). 37326340
BRAF V600E colorectal carcinoma sensitive Gedatolisib + Palbociclib Preclinical - Cell culture Actionable In a preclinical study, the combination of Ibrance (palbociclib) and Gedatolisib (PF-05212384) synergistically inhibited growth of a colorectal carcinoma cell line harboring BRAF V600E in culture (PMID: 37326340). 37326340
BRAF V600E colorectal carcinoma no benefit Palbociclib + PD-0325901 Preclinical - Cell culture Actionable In a preclinical study, the combination of Ibrance (palbociclib) and PD-0325901 demonstrated antagonism in a colorectal carcinoma cell line harboring BRAF V600E in culture (PMID: 37326340). 37326340
PIK3CA E545G colorectal adenocarcinoma sensitive Palbociclib + PD-0325901 Preclinical - Cell culture Actionable In a preclinical study, the combination of Ibrance (palbociclib) and PD-0325901 synergistically inhibited growth of a colorectal adenocarcinoma cell line harboring PIK3CA E545G in culture (PMID: 37326340). 37326340