title: Simultaneous exposure of transformed cells to SRC family inhibitors and CHK1 inhibitors causes cell death.
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.
authors.affiliation: Department of Neurosurgery, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
authors.forename: Clint
authors.initials: C
authors.lastname: Mitchell
authors.forename: Hossein A
authors.initials: HA
authors.lastname: Hamed
authors.forename: Nichola
authors.initials: N
authors.lastname: Cruickshanks
authors.forename: Yong
authors.initials: Y
authors.lastname: Tang
authors.forename: M Danielle
authors.initials: MD
authors.lastname: Bareford
authors.forename: Nissan
authors.initials: N
authors.lastname: Hubbard
authors.forename: Gary
authors.initials: G
authors.lastname: Tye
authors.forename: Adly
authors.initials: A
authors.lastname: Yacoub
authors.forename: Yun
authors.initials: Y
authors.lastname: Dai
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D000071877:Checkpoint Kinase 1; D000069439:Dasatinib; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D051379:Mice; D011480:Protease Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics; D051575:Proto-Oncogene Proteins c-yes / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D011836:Radiation Tolerance; D013844:Thiazoles / Q000494:pharmacology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: C412373:AG 1879; C517975:AZD 6244; C494772:BAK1 protein, human; D001562:Benzimidazoles; D052117:Benzodioxoles; D011480:Protease Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D013844:Thiazoles; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C515233:saracatinib; D011494:Protein Kinases; C482128:MAP2K2 protein, human; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D051575:Proto-Oncogene Proteins c-yes; C496639:Yes1 protein, mouse; D019061:src-Family Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D000069439:Dasatinib