PAK kinase inhibition has therapeutic activity in novel preclinical models of adult T-Cell leukemia/lymphoma

Elaine Y. L. Chung, Yun Mai, Urvi A. Shah, Yongqiang Wei, Elise Ishida, Keisuke Kataoka, Xiaoxin Ren, Kith Pradhan, Boris A. Bartholdy, Xiaolei Wei, Yiyu Zou, Jinghang Zhang, Seishi Ogawa, Ulrich G. Steidl, Xingxing Zang, Amit K. Verma, Murali Janakiram, B. Hilda Ye

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Abstract

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 ATLLsandare associated withworse 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.

Original languageEnglish (US)
Pages (from-to)3589-3601
Number of pages13
JournalClinical Cancer Research
Volume25
Issue number12
DOIs
StatePublished - Jun 15 2019

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p21-Activated Kinases
Adult T Cell Leukemia Lymphoma
Therapeutics
Cell Survival
Protein Isoforms
Inhibition (Psychology)
Aptitude
Gene Silencing
Heterografts
Cell Adhesion
Small Interfering RNA
Research Design

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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PAK kinase inhibition has therapeutic activity in novel preclinical models of adult T-Cell leukemia/lymphoma. / Chung, Elaine Y. L.; Mai, Yun; Shah, Urvi A.; Wei, Yongqiang; Ishida, Elise; Kataoka, Keisuke; Ren, Xiaoxin; Pradhan, Kith; Bartholdy, Boris A.; Wei, Xiaolei; Zou, Yiyu; Zhang, Jinghang; Ogawa, Seishi; Steidl, Ulrich G.; Zang, Xingxing; Verma, Amit K.; Janakiram, Murali; Ye, B. Hilda.

In: Clinical Cancer Research, Vol. 25, No. 12, 15.06.2019, p. 3589-3601.

Research output: Contribution to journalArticle

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title = "PAK kinase inhibition has therapeutic activity in novel preclinical models of adult T-Cell leukemia/lymphoma",
abstract = "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 ATLLsandare associated withworse 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.",
author = "Chung, {Elaine Y. L.} and Yun Mai and Shah, {Urvi A.} and Yongqiang Wei and Elise Ishida and Keisuke Kataoka and Xiaoxin Ren and Kith Pradhan and Bartholdy, {Boris A.} and Xiaolei Wei and Yiyu Zou and Jinghang Zhang and Seishi Ogawa and Steidl, {Ulrich G.} and Xingxing Zang and Verma, {Amit K.} and Murali Janakiram and Ye, {B. Hilda}",
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T1 - PAK kinase inhibition has therapeutic activity in novel preclinical models of adult T-Cell leukemia/lymphoma

AU - Chung, Elaine Y. L.

AU - Mai, Yun

AU - Shah, Urvi A.

AU - Wei, Yongqiang

AU - Ishida, Elise

AU - Kataoka, Keisuke

AU - Ren, Xiaoxin

AU - Pradhan, Kith

AU - Bartholdy, Boris A.

AU - Wei, Xiaolei

AU - Zou, Yiyu

AU - Zhang, Jinghang

AU - Ogawa, Seishi

AU - Steidl, Ulrich G.

AU - Zang, Xingxing

AU - Verma, Amit K.

AU - Janakiram, Murali

AU - Ye, B. Hilda

PY - 2019/6/15

Y1 - 2019/6/15

N2 - 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 ATLLsandare associated withworse 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.

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 ATLLsandare associated withworse 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.

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U2 - 10.1158/1078-0432.CCR-18-3033

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JO - Clinical Cancer Research

JF - Clinical Cancer Research

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ER -