| RRC ID |
57867
|
| 著者 |
Caumanns JJ, van Wijngaarden A, Kol A, Meersma GJ, Jalving M, Bernards R, van der Zee AGJ, Wisman GBA, de Jong S.
|
| タイトル |
Low-dose triple drug combination targeting the PI3K/AKT/mTOR pathway and the MAPK pathway is an effective approach in ovarian clear cell carcinoma.
|
| ジャーナル |
Cancer Lett
|
| Abstract |
Advanced stage ovarian clear cell carcinoma (OCCC) is poorly responsive to platinum-based chemotherapy and has an unfavorable prognosis. Previous studies revealed heterogeneous mutations in PI3K/AKT/mTOR and MAPK pathway nodules converging in mTORC1/2 activation. Here, we aimed to identify an effective low-dose combination of PI3K/AKT/mTOR pathway and MAPK pathway inhibitors simultaneously targeting key kinases in OCCC to preclude single-inhibitor initiated pathway rewiring and limit toxicity. Small molecule inhibitors of mTORC1/2, PI3K and MEK1/2 were combined at monotherapy IC20 doses in a panel of genetically diverse OCCC cell lines (n = 7) to determine an optimal low-dose combination. The IC20 dose triple combination reduced kinase activity in PI3K/AKT/mTOR and MAPK pathways, prevented single-inhibitor induced feedback mechanisms and inhibited short and long-term proliferation in all seven cell lines. Finally, this low-dose triple drug combination treatment significantly reduced tumor growth in two genetically characterized OCCC patient-derived xenograft (PDX) models without resulting in weight loss in these mice. The effectiveness and tolerability of this combined therapy in PDX models warrants clinical exploration of this treatment strategy for OCCC and might be applicable to other cancer types with a similar genetic background.
|
| 巻・号 |
461
|
| ページ |
102-111
|
| 公開日 |
2019-10-1
|
| DOI |
10.1016/j.canlet.2019.07.004
|
| PII |
S0304-3835(19)30400-8
|
| PMID |
31319139
|
| MeSH |
Adenocarcinoma, Clear Cell / drug therapy*
Adenocarcinoma, Clear Cell / metabolism
Adenocarcinoma, Clear Cell / pathology
Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis
Benzimidazoles / administration & dosage
Benzoxazoles / administration & dosage
Biomarkers, Tumor
Cell Proliferation
Dose-Response Relationship, Drug
Drug Synergism
Female
Gene Expression Regulation, Neoplastic / drug effects*
Humans
Indazoles / administration & dosage
Mice
Mice, Nude
Morpholines / administration & dosage
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / metabolism
Ovarian Neoplasms / pathology
Phosphatidylinositol 3-Kinases / chemistry*
Phosphorylation
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Pyrimidines / administration & dosage
Sulfonamides / administration & dosage
TOR Serine-Threonine Kinases / antagonists & inhibitors*
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
|
| IF |
7.36
|
| 引用数 |
10
|
| リソース情報 |
| ヒト・動物細胞 |
JHOC-5(RCB1520) |
