TY - JOUR
T1 - The ALK inhibitor ASP3026 eradicates NPM-ALK+ T-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model
AU - George, Suraj Konnath
AU - Vishwamitra, Deeksha
AU - Manshouri, Roxsan
AU - Shi, Ping
AU - Amin, Hesham M.
PY - 2014
Y1 - 2014
N2 - NPM-ALK+ T-cell anaplastic large-cell lymphoma (ALCL) is an aggressive type of cancer. Standard treatment of NPM-ALK+ ALCL is CHOP polychemotherapy. Although patients initially respond favorably to CHOP, resistance, relapse, and death frequently occur. Recently, selective targeting of ALK has emerged as an alternative therapeutic strategy. ASP3026 is a second-generation ALK inhibitor that can overcome crizotinib resistance in non-small cell lung cancer, and is currently being evaluated in clinical trials of patients with ALK+ solid tumors. However, NPM-ALK+ ALCL patients are not included in these trials. We studied the effects of ASP3026 on NPM-ALK+ ALCL cell lines in vitro and on systemic lymphoma growth in vivo. ASP3026 decreased the viability, proliferation, and colony formation, as well as induced apoptotic cell death of NPM-ALK+ ALCL cells. In addition, ASP3026 significantly reduced the proliferation of 293T cells transfected with NPM-ALK mutants that are resistant to crizotinib and downregulated tyrosine phosphorylation of these mutants. Moreover, ASP3026 abrogated systemic NPM-ALK+ ALCL growth in mice. Importantly, the survival of ASP3026-treated mice was superior to that of control and CHOP-treated mice. Our data suggest that ASP3026 is an effective treatment for NPM-ALK+ ALCL, and support the enrollment of patients with this lymphoma in the ongoing clinical trials.
AB - NPM-ALK+ T-cell anaplastic large-cell lymphoma (ALCL) is an aggressive type of cancer. Standard treatment of NPM-ALK+ ALCL is CHOP polychemotherapy. Although patients initially respond favorably to CHOP, resistance, relapse, and death frequently occur. Recently, selective targeting of ALK has emerged as an alternative therapeutic strategy. ASP3026 is a second-generation ALK inhibitor that can overcome crizotinib resistance in non-small cell lung cancer, and is currently being evaluated in clinical trials of patients with ALK+ solid tumors. However, NPM-ALK+ ALCL patients are not included in these trials. We studied the effects of ASP3026 on NPM-ALK+ ALCL cell lines in vitro and on systemic lymphoma growth in vivo. ASP3026 decreased the viability, proliferation, and colony formation, as well as induced apoptotic cell death of NPM-ALK+ ALCL cells. In addition, ASP3026 significantly reduced the proliferation of 293T cells transfected with NPM-ALK mutants that are resistant to crizotinib and downregulated tyrosine phosphorylation of these mutants. Moreover, ASP3026 abrogated systemic NPM-ALK+ ALCL growth in mice. Importantly, the survival of ASP3026-treated mice was superior to that of control and CHOP-treated mice. Our data suggest that ASP3026 is an effective treatment for NPM-ALK+ ALCL, and support the enrollment of patients with this lymphoma in the ongoing clinical trials.
KW - ASP3026
KW - CHOP
KW - Crizotinib
KW - NPM-ALK
KW - T-cell lymphoma
UR - http://www.scopus.com/inward/record.url?scp=84906220978&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84906220978&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.2170
DO - 10.18632/oncotarget.2170
M3 - Article
C2 - 25026277
AN - SCOPUS:84906220978
SN - 1949-2553
VL - 5
SP - 5750
EP - 5763
JO - Oncotarget
JF - Oncotarget
IS - 14
ER -