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Low-dose triple drug combination targeting the PI3K/AKT/mTOR pathway and the MAPK pathway is an effective approach in ovarian clear cell carcinoma
- Source :
- Cancer letters, 461, 102-111. ELSEVIER IRELAND LTD
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
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.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
Cancer Research
Indazoles
Morpholines
Mice, Nude
Apoptosis
mTORC1
Mice
Phosphatidylinositol 3-Kinases
03 medical and health sciences
0302 clinical medicine
Antineoplastic Combined Chemotherapy Protocols
Biomarkers, Tumor
Tumor Cells, Cultured
Animals
Humans
Medicine
Phosphorylation
Kinase activity
Protein Kinase Inhibitors
Protein kinase B
PI3K/AKT/mTOR pathway
Cell Proliferation
Ovarian Neoplasms
Benzoxazoles
Sulfonamides
Dose-Response Relationship, Drug
business.industry
Kinase
TOR Serine-Threonine Kinases
Cancer
Drug Synergism
medicine.disease
Xenograft Model Antitumor Assays
Gene Expression Regulation, Neoplastic
Pyrimidines
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Clear cell carcinoma
Cancer research
Benzimidazoles
Female
business
Proto-Oncogene Proteins c-akt
Adenocarcinoma, Clear Cell
Subjects
Details
- ISSN :
- 03043835
- Volume :
- 461
- Database :
- OpenAIRE
- Journal :
- Cancer Letters
- Accession number :
- edsair.doi.dedup.....e959c3d1933113e4c2201bc98d76c759