title: Targeting p21-activated kinase 1 (PAK1) to induce apoptosis of tumor cells.
abstract: p21-activated kinases (PAKs) are serine/threonine protein kinases that serve as important mediators of Rac and Cdc42 GTPase function as well as pathways required for Ras-driven tumorigenesis. PAK1 has been implicated in signaling by growth factor receptors and morphogenetic processes that control cell polarity, invasion, and actin cytoskeleton organization. To better understand the role of PAK1 in tumorigenesis, PAK1 genomic copy number and expression were determined for a large panel of breast, lung, and head and neck tumors. PAK1 genomic amplification at 11q13 was prevalent in luminal breast cancer, and PAK1 protein expression was associated with lymph node metastasis. Breast cancer cells with PAK1 genomic amplification rapidly underwent apoptosis after inhibition of this kinase. Strong nuclear and cytoplasmic PAK1 expression was also prevalent in squamous nonsmall cell lung carcinomas (NSCLCs), and selective PAK1 inhibition was associated with delayed cell-cycle progression in vitro and in vivo. NSCLC cells were profiled using a library of pathway-targeted small-molecule inhibitors, and several synergistic combination therapies, including combination with antagonists of inhibitor of apoptosis proteins, were revealed for PAK1. Dual inhibition of PAK1 and X chromosome-linked inhibitor of apoptosis efficiently increased effector caspase activation and apoptosis of NSCLC cells. Together, our results provide evidence for dysregulation of PAK1 in breast and squamous NSCLCs and a role for PAK1 in cellular survival and proliferation in these indications.
authors.affiliation: Department of Translational Oncology, Genentech, Inc, South San Francisco, CA 94080, USA.
authors.forename: Christy C
authors.initials: CC
authors.lastname: Ong
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Jubb
authors.forename: Peter M
authors.initials: PM
authors.lastname: Haverty
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Victoria
authors.initials: V
authors.lastname: Tran
authors.forename: Tom
authors.initials: T
authors.lastname: Truong
authors.forename: Helen
authors.initials: H
authors.lastname: Turley
authors.forename: Tom
authors.initials: T
authors.lastname: O'Brien
authors.forename: Domagoj
authors.initials: D
authors.lastname: Vucic
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Marcia
authors.initials: M
authors.lastname: Belvin
authors.forename: Lori S
authors.initials: LS
authors.lastname: Friedman
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Blackwood
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Hoeflich
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008198:Lymph Nodes / Q000201:enzymology / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D020169:Caspases