Abstract 2876: p21-activated kinase 1 is a novel therapeutic target for metastatic osteosarcoma harboring p27 mislocalization

Abstract

Lung metastasis is the leading cause of death in osteosarcoma (OS), the most common bone cancer in children and young adults. Due to a lack of biomarkers and therapeutic targets, significant progress has not been made in the treatment of metastatic OS over the past three decades. The survival of metastatic patients remains dismal. We have previously reported that the tumor suppressor protein p27 (KIP1, CDKN1B) is frequently mislocalized in the cytoplasm of OS, which promotes the motility and invasiveness of the tumor cells and the development of pulmonary metastases in mice. In this study, we showed that a higher proportion score of cytoplasmic p27 significantly correlated with metastases developed within 3- or 5-year of follow-up, and poor disease-specific and event-free survival in a large OS cohort (n=136). Using immunoprecipitation followed by mass spectrometry, we demonstrated that cytoplasmic p27 interacted with p21-activated kinase 1 (PAK1), where the two proteins co-localized in the cytoplasm of OS cells. PAK1 is a serine/threonine kinase that has been implicated in various cancers; however, its role in OS is still elusive. We showed that the phosphorylations at serine-144 and threonine-423 residues of PAK1 were higher in the p27-mislocalized cells relative to the control cells. The PAK1 phosphorylations increased actin stress fiber formation in the tumor cells. Gene silencing or therapeutic inhibition of PAK1 reduced the motility of p27-mislocalized cells in vitro . Similar results were observed in other cancer cell lines known to have the p27 mislocalization, suggesting PAK1 is a common and potential downstream effector of p27-mediated metastasis. An experimental metastasis mouse model further showed that a PAK1-silenced mutant had a significant impairment in the development of pulmonary metastasis. In summary, our study indicates that cytoplasmic p27 is a novel prognostic biomarker in OS. In the tumor cell, the mislocalization activates PAK1-mediated cell motility and metastasis. Targeting PAK1 in metastatic OS harboring the p27 mislocalization may be exploited as a potential therapeutic intervention to improve the poor outcome of the affected children. Citation Format: Xiang Chen, Justin Cates, Yuchen Du, Yun Jung Sung, Xiao-nan Lo, John Hicks, Tsz-Kwong Man. p21-activated kinase 1 is a novel therapeutic target for metastatic osteosarcoma harboring p27 mislocalization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2876.