title: p21-Activated kinase 1 is required for efficient tumor formation and progression in a Ras-mediated skin cancer model.
abstract: The RAS genes are the most commonly mutated oncogenes in human cancer and present a particular therapeutic dilemma, as direct targeting of Ras proteins by small molecules has proved difficult. Signaling pathways downstream of Ras, in particular Raf/Mek/Erk and PI3K/Akt/mTOR, are dominated by lipid and protein kinases that provide attractive alternate targets in Ras-driven tumors. As p21-activated kinase 1 (Pak1) has been shown to regulate both these signaling pathways and is itself upregulated in many human cancers, we assessed the role of Pak1 in Ras-driven skin cancer. In human squamous cell carcinoma (SCC), we found a strong positive correlation between advanced stage and grade and PAK1 expression. Using a mouse model of Kras-driven SCC, we showed that deletion of the mouse Pak1 gene led to markedly decreased tumorigenesis and progression, accompanied by near total loss of Erk and Akt activity. Treatment of Kras(G12D) mice with either of two distinct small molecule Pak inhibitors (PF3758309 and FRAX597) caused tumor regression and loss of Erk and Akt activity. Tumor regression was also seen in mice treated with a specific Mek inhibitor, but not with an Akt inhibitor. These findings establish Pak1 as a new target in KRAS-driven tumors and suggest a mechanism of action through the Erk, but not the Akt, signaling pathway.
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
authors.forename: Hoi Yee
authors.initials: HY
authors.lastname: Chow
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Jubb
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Koch
authors.forename: Zahara M
authors.initials: ZM
authors.lastname: Jaffer
authors.forename: Dina
authors.initials: D
authors.lastname: Stepanova
authors.forename: David A
authors.initials: DA
authors.lastname: Campbell
authors.forename: Sergio G
authors.initials: SG
authors.lastname: Duron
authors.forename: Marie
authors.initials: M
authors.lastname: O'Farrell
authors.forename: Kathy Q
authors.initials: KQ
authors.lastname: Cai
authors.forename: Andres J P
authors.initials: AJ
authors.lastname: Klein-Szanto
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Hoeflich
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chernoff
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017353:Gene Deletion; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D051058:Oncogene Protein v-akt / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D011728:Pyridones / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C584676:FRAX597; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011728:Pyridones; D011743:Pyrimidines; D051058:Oncogene Protein v-akt; C515903:PAK1 protein, human; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins