American Association for Cancer Research
Browse
10780432ccr183033-sup-208840_2_supp_5362882_pncnfr.pptx (55.29 kB)

Supplementary Tables from PAK Kinase Inhibition Has Therapeutic Activity in Novel Preclinical Models of Adult T-Cell Leukemia/Lymphoma

Download (55.29 kB)
figure
posted on 2023-03-31, 20:44 authored by Elaine Y. Chung, Yun Mai, Urvi A. Shah, Yongqiang Wei, Elise Ishida, Keisuke Kataoka, Xiaoxin Ren, Kith Pradhan, Boris Bartholdy, Xiaolei Wei, Yiyu Zou, Jinghang Zhang, Seishi Ogawa, Ulrich Steidl, Xingxing Zang, Amit Verma, Murali Janakiram, B. Hilda Ye

Supplementary Tables Table S1. List of antibodies used in Western blotting and flow cytometry analyses. Table S2. List of qRT-PCR primers.

Funding

NIH

NCI

NYSTEM

Leukaemia and Lymphoma Research

Louis Skarlow Memorial Trust

Aids Malignancy Consortium

Harry Eagle Scholarship from the Department of Cell Biology, Albert Einstein College of Medicine, and U.A.

History

ARTICLE ABSTRACT

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. 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. 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. 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.

Usage metrics

    Clinical Cancer Research

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC