Abstract
The present studies were initiated to determine in greater molecular detail the regulation of CHK1 inhibitor lethality in transfected and infected breast cancer cells and using genetic models of transformed fibrobalsts. Multiple MEK1/2 inhibitors (PD184352, AZD6244 (ARRY-142886)) interacted with multiple CHK1 inhibitors (UCN-01 (7-hydroxystaurosporine), AZD7762) to kill mammary carcinoma cells and transformed fibroblasts. In transformed cells, CHK1 inhibitor -induced activation of ERK1/2 was dependent upon activation of SRC family non-receptor tyrosine kinases as judged by use of multiple SRC kinase inhibitors (PP2, Dasatinib; AZD0530), use of SRC/FYN/YES deleted transformed fibroblasts or by expression of dominant negative SRC. Cell killing by SRC family kinase inhibitors and CHK1 inhibitors was abolished in BAX/BAK -/- transformed fibroblasts and suppressed by over expression of BCL-XL. Treatment of cells with BCL-2/BCL-XL antagonists promoted SRC inhibitor + CHK1 inhibitor -induced lethality in a BAX/BAK-dependent fashion. Treatment of cells with [SRC + CHK1] inhibitors radio-sensitized tumor cells. These findings argue that multiple inhibitors of the SRC-RAS-MEK pathway interact with multiple CHK1 inhibitors to kill transformed cells.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Animals
-
Benzimidazoles / pharmacology
-
Benzodioxoles / pharmacology
-
Breast Neoplasms / genetics
-
Breast Neoplasms / metabolism
-
Breast Neoplasms / pathology*
-
Cell Death / drug effects
-
Cell Line, Transformed
-
Cell Transformation, Neoplastic
-
Checkpoint Kinase 1
-
Dasatinib
-
Female
-
Fibroblasts / pathology
-
Humans
-
MAP Kinase Kinase 1 / antagonists & inhibitors
-
MAP Kinase Kinase 2 / antagonists & inhibitors
-
Mice
-
Protease Inhibitors / pharmacology*
-
Protein Kinases / metabolism*
-
Proto-Oncogene Proteins c-fyn / genetics
-
Proto-Oncogene Proteins c-yes / genetics
-
Pyrimidines / pharmacology
-
Quinazolines / pharmacology
-
Radiation Tolerance
-
Thiazoles / pharmacology
-
bcl-2 Homologous Antagonist-Killer Protein / genetics
-
bcl-2-Associated X Protein / genetics
-
bcl-X Protein / antagonists & inhibitors
-
bcl-X Protein / genetics
-
bcl-X Protein / metabolism
-
src-Family Kinases / antagonists & inhibitors*
Substances
-
AG 1879
-
AZD 6244
-
BAK1 protein, human
-
Benzimidazoles
-
Benzodioxoles
-
Protease Inhibitors
-
Pyrimidines
-
Quinazolines
-
Thiazoles
-
bcl-2 Homologous Antagonist-Killer Protein
-
bcl-2-Associated X Protein
-
bcl-X Protein
-
saracatinib
-
Protein Kinases
-
MAP2K2 protein, human
-
Fyn protein, mouse
-
Proto-Oncogene Proteins c-fyn
-
Proto-Oncogene Proteins c-yes
-
Yes1 protein, mouse
-
src-Family Kinases
-
CHEK1 protein, human
-
Checkpoint Kinase 1
-
Chek1 protein, mouse
-
MAP Kinase Kinase 1
-
MAP Kinase Kinase 2
-
MAP2K1 protein, human
-
Dasatinib