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	Clint Mitchell, Hossein A Hamed, Nichola Cruickshanks, Yong Tang, M Danielle Bareford, Nissan Hubbard, Gary Tye, Adly Yacoub, Yun Dai, Steven Grant, Paul Dent
Journal	Cancer biology & therapy (Cancer Biol Ther) Vol. 12 Issue 3 Pg. 215-28 (Aug 01 2011) ISSN: 1555-8576 [Electronic] United States
PMID	21642769 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References	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
Topics	Animals Benzimidazoles (pharmacology) Benzodioxoles (pharmacology) Breast Neoplasms (genetics, metabolism, 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, genetics, metabolism) src-Family Kinases (antagonists & inhibitors)

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