Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer biology & therapy	24	1	2023 Dec 31	2223388	Cancer Biol Ther

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
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
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
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
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