TY - JOUR
T1 - Small molecule inhibition of group I p21-activated kinases in breast cancer induces apoptosis and potentiates the activity of microtubule stabilizing agents
AU - Ong, Christy C.
AU - Gierke, Sarah
AU - Pitt, Cameron
AU - Sagolla, Meredith
AU - Cheng, Christine K.
AU - Zhou, Wei
AU - Jubb, Adrian M.
AU - Strickland, Laura
AU - Schmidt, Maike
AU - Duron, Sergio G.
AU - Campbell, David A.
AU - Zheng, Wei
AU - Dehdashti, Seameen
AU - Shen, Min
AU - Yang, Nora
AU - Behnke, Mark L.
AU - Huang, Wenwei
AU - McKew, John C.
AU - Chernoff, Jonathan
AU - Forrest, William F.
AU - Haverty, Peter M.
AU - Chin, Suet Feung
AU - Rakha, Emad A.
AU - Green, Andrew R.
AU - Ellis, Ian O.
AU - Caldas, Carlos
AU - O'Brien, Thomas
AU - Friedman, Lori S.
AU - Koeppen, Hartmut
AU - Rudolph, Joachim
AU - Hoeflich, Klaus P.
N1 - Publisher Copyright:
© 2015 Ong et al.; licensee BioMed Central.
PY - 2015/3/23
Y1 - 2015/3/23
N2 - Introduction: Breast cancer, the most common cause of cancer-related deaths worldwide among women, is a molecularly and clinically heterogeneous disease. Extensive genetic and epigenetic profiling of breast tumors has recently revealed novel putative driver genes, including p21-activated kinase (PAK)1. PAK1 is a serine/threonine kinase downstream of small GTP-binding proteins, Rac1 and Cdc42, and is an integral component of growth factor signaling networks and cellular functions fundamental to tumorigenesis. Methods: PAK1 dysregulation (copy number gain, mRNA and protein expression) was evaluated in two cohorts of breast cancer tissues (n = 980 and 1,108). A novel small molecule inhibitor, FRAX1036, and RNA interference were used to examine PAK1 loss of function and combination with docetaxel in vitro. Mechanism of action for the therapeutic combination, both cellular and molecular, was assessed via time-lapse microscopy and immunoblotting. Results: We demonstrate that focal genomic amplification and overexpression of PAK1 are associated with poor clinical outcome in the luminal subtype of breast cancer (P = 1.29 × 10-4 and P = 0.015, respectively). Given the role for PAK1 in regulating cytoskeletal organization, we hypothesized that combination of PAK1 inhibition with taxane treatment could be combined to further interfere with microtubule dynamics and cell survival. Consistent with this, administration of docetaxel with either a novel small molecule inhibitor of group I PAKs, FRAX1036, or PAK1 small interfering RNA oligonucleotides dramatically altered signaling to cytoskeletal-associated proteins, such as stathmin, and induced microtubule disorganization and cellular apoptosis. Live-cell imaging revealed that the duration of mitotic arrest mediated by docetaxel was significantly reduced in the presence of FRAX1036, and this was associated with increased kinetics of apoptosis. Conclusions: Taken together, these findings further support PAK1 as a potential target in breast cancer and suggest combination with taxanes as a viable strategy to increase anti-tumor efficacy.
AB - Introduction: Breast cancer, the most common cause of cancer-related deaths worldwide among women, is a molecularly and clinically heterogeneous disease. Extensive genetic and epigenetic profiling of breast tumors has recently revealed novel putative driver genes, including p21-activated kinase (PAK)1. PAK1 is a serine/threonine kinase downstream of small GTP-binding proteins, Rac1 and Cdc42, and is an integral component of growth factor signaling networks and cellular functions fundamental to tumorigenesis. Methods: PAK1 dysregulation (copy number gain, mRNA and protein expression) was evaluated in two cohorts of breast cancer tissues (n = 980 and 1,108). A novel small molecule inhibitor, FRAX1036, and RNA interference were used to examine PAK1 loss of function and combination with docetaxel in vitro. Mechanism of action for the therapeutic combination, both cellular and molecular, was assessed via time-lapse microscopy and immunoblotting. Results: We demonstrate that focal genomic amplification and overexpression of PAK1 are associated with poor clinical outcome in the luminal subtype of breast cancer (P = 1.29 × 10-4 and P = 0.015, respectively). Given the role for PAK1 in regulating cytoskeletal organization, we hypothesized that combination of PAK1 inhibition with taxane treatment could be combined to further interfere with microtubule dynamics and cell survival. Consistent with this, administration of docetaxel with either a novel small molecule inhibitor of group I PAKs, FRAX1036, or PAK1 small interfering RNA oligonucleotides dramatically altered signaling to cytoskeletal-associated proteins, such as stathmin, and induced microtubule disorganization and cellular apoptosis. Live-cell imaging revealed that the duration of mitotic arrest mediated by docetaxel was significantly reduced in the presence of FRAX1036, and this was associated with increased kinetics of apoptosis. Conclusions: Taken together, these findings further support PAK1 as a potential target in breast cancer and suggest combination with taxanes as a viable strategy to increase anti-tumor efficacy.
KW - Apoptosis/drug effects
KW - Breast Neoplasms/genetics
KW - Cell Cycle Checkpoints/drug effects
KW - Cell Line, Tumor
KW - DNA Copy Number Variations
KW - Docetaxel
KW - Drug Synergism
KW - Female
KW - Gene Amplification
KW - Gene Expression
KW - Humans
KW - Microtubules/metabolism
KW - Prognosis
KW - Protein Kinase Inhibitors/pharmacology
KW - Signal Transduction/drug effects
KW - Taxoids/pharmacology
KW - Tubulin Modulators/pharmacology
KW - p21-Activated Kinases/antagonists & inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85019251170&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000355092100001&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1186/s13058-015-0564-5
DO - 10.1186/s13058-015-0564-5
M3 - Article
C2 - 25902869
SN - 1465-5411
VL - 17
SP - 59
JO - Breast Cancer Research
JF - Breast Cancer Research
IS - 1
M1 - 59
ER -