PMID- 30862694 OWN - NLM STAT- MEDLINE DCOM- 20200819 LR - 20200819 IS - 1557-3265 (Electronic) IS - 1078-0432 (Linking) VI - 25 IP - 12 DP - 2019 Jun 15 TI - PAK Kinase Inhibition Has Therapeutic Activity in Novel Preclinical Models of Adult T-Cell Leukemia/Lymphoma. PG - 3589-3601 LID - 10.1158/1078-0432.CCR-18-3033 [doi] AB - PURPOSE: To evaluate therapeutic activity of PAK inhibition in ATLL and to characterize the role of PAK isoforms in cell proliferation, survival, and adhesion of ATLL cells in preclinical models. EXPERIMENTAL DESIGN: Frequency and prognostic impact of PAK2 amplification were evaluated in an ATLL cohort of 370 cases. Novel long-term cultures and in vivo xenograft models were developed using primary ATLL cells from North American patients. Two PAK inhibitors were used to block PAK kinase activity pharmacologically. siRNA-based gene silencing approach was used to genetically knockdown (KD) PAK1 and PAK2 in ATLL cell lines. RESULTS: PAK1/2/4 are the three most abundantly expressed PAK family members in ATLL. PAK2 amplifications are seen in 24% of ATLLs and are associated with worse prognosis in a large patient cohort. The pan-PAK inhibitor PF-3758309 (PF) has strong in vitro and in vivo activity in a variety of ATLL preclinical models. These activities of PF are likely attributed to its ability to target several PAK isoforms simultaneously because genetic silencing of either PAK1 or PAK2 produced more modest effects. PAK2 plays a major role in CADM1-mediated stromal interaction, which is an important step in systemic dissemination of the disease. This finding is consistent with the observation that PAK2 amplification is more frequent in aggressive ATLLs and correlates with inferior outcome. CONCLUSIONS: PAK2, a gene frequently amplified in ATLL, facilitates CADM1-mediated stromal interaction and promotes survival of ATLL cells. Taken together, PAK inhibition may hold significant promise as a targeted therapy for aggressive ATLLs. CI - (c)2019 American Association for Cancer Research. FAU - Chung, Elaine Y AU - Chung EY AD - Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York. FAU - Mai, Yun AU - Mai Y AD - Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York. FAU - Shah, Urvi A AU - Shah UA AUID- ORCID: 0000-0001-8419-1091 AD - Department of Oncology, Montefiore Medical Center, Bronx, New York. FAU - Wei, Yongqiang AU - Wei Y AD - Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York. AD - Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China. FAU - Ishida, Elise AU - Ishida E AD - Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York. FAU - Kataoka, Keisuke AU - Kataoka K AD - Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan. FAU - Ren, Xiaoxin AU - Ren X AD - Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York. FAU - Pradhan, Kith AU - Pradhan K AD - Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York. FAU - Bartholdy, Boris AU - Bartholdy B AUID- ORCID: 0000-0002-7401-8591 AD - Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York. FAU - Wei, Xiaolei AU - Wei X AD - Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York. AD - Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China. FAU - Zou, Yiyu AU - Zou Y AD - Department of Oncology, Montefiore Medical Center, Bronx, New York. FAU - Zhang, Jinghang AU - Zhang J AD - Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York. FAU - Ogawa, Seishi AU - Ogawa S AD - Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan. FAU - Steidl, Ulrich AU - Steidl U AD - Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York. FAU - Zang, Xingxing AU - Zang X AD - Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York. FAU - Verma, Amit AU - Verma A AD - Department of Oncology, Montefiore Medical Center, Bronx, New York. AD - Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York. FAU - Janakiram, Murali AU - Janakiram M AD - Department of Oncology, Montefiore Medical Center, Bronx, New York. FAU - Ye, B Hilda AU - Ye BH AD - Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York. hilda.ye@einstein.yu.edu. LA - eng GR - P30 CA013330/CA/NCI NIH HHS/United States GR - UM1 CA121947/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20190312 PL - United States TA - Clin Cancer Res JT - Clinical cancer research : an official journal of the American Association for Cancer Research JID - 9502500 RN - 0 (CADM1 protein, human) RN - 0 (Cell Adhesion Molecule-1) RN - 0 (PF 3758309) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrazoles) RN - 0 (Pyrroles) RN - 0 (RNA, Small Interfering) RN - EC 2.7.11.1 (PAK2 protein, human) RN - EC 2.7.11.1 (p21-Activated Kinases) SB - IM MH - Adult MH - Animals MH - Cell Adhesion/drug effects MH - Cell Adhesion Molecule-1/metabolism MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Female MH - Gene Amplification MH - Humans MH - Leukemia-Lymphoma, Adult T-Cell/*drug therapy/genetics/metabolism/pathology MH - Mice MH - Mice, Inbred NOD MH - Mice, SCID MH - Primary Cell Culture MH - Protein Kinase Inhibitors/*pharmacology MH - Pyrazoles/*pharmacology MH - Pyrroles/*pharmacology MH - RNA, Small Interfering/genetics MH - Survival Rate MH - Xenograft Model Antitumor Assays MH - p21-Activated Kinases/*antagonists & inhibitors/genetics EDAT- 2019/03/14 06:00 MHDA- 2020/08/20 06:00 CRDT- 2019/03/14 06:00 PHST- 2018/09/14 00:00 [received] PHST- 2019/01/11 00:00 [revised] PHST- 2019/03/06 00:00 [accepted] PHST- 2019/03/14 06:00 [pubmed] PHST- 2020/08/20 06:00 [medline] PHST- 2019/03/14 06:00 [entrez] AID - 1078-0432.CCR-18-3033 [pii] AID - 10.1158/1078-0432.CCR-18-3033 [doi] PST - ppublish SO - Clin Cancer Res. 2019 Jun 15;25(12):3589-3601. doi: 10.1158/1078-0432.CCR-18-3033. Epub 2019 Mar 12.