Crizotinib (PF-2341066) induces apoptosis due to downregulation of pSTAT3 and BCL-2 family proteins in NPM-ALK(+) anaplastic large cell lymphoma.

Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is an aberrant fusion gene product with tyrosine kinase activity and is expressed in substantial subset of anaplastic large cell lymphomas (ALCL). It has been shown that NPM-ALK binds to and activates signal transducer and activator of transcription 3 (STAT3). Although NPM-ALK(+) ALCL overall shows a better prognosis, there is a sub-group of patients who relapses and is resistant to conventional chemotherapeutic regimens. NPM-ALK is a potential target for small molecule kinase inhibitors. Crizotinib (PF-2341066) is a small, orally bioavailable molecule that inhibits growth of tumors with ALK activity as shown in a subgroup of non-small lung cancer patients with EML4-ALK expression. In this study, we have investigated the in vitro effects of Crizotinib in ALCL cell line with NPM-ALK fusion. Crizotinib induced marked downregulation of STAT3 phosphorylation, which was associated with significant apoptotic cell death. Apoptosis induction was attributed to caspase-3 cleavage and marked downregulation of the Bcl-2 family of proteins including MCL-1. These findings implicate that Crizotinib has excellent potential to treat patients with NPM-ALK(+) ALCL through induction of apoptotic cell death and downregulation of major oncogenic proteins in this aggressive lymphoma.

Hamedani FS ，Cinar M ，Mo Z ，Cervania MA ，Amin HM ，Alkan S ... -  《-》

Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma.

Christensen JG ，Zou HY ，Arango ME ，Li Q ，Lee JH ，McDonnell SR ，Yamazaki S ，Alton GR ，Mroczkowski B ，Los G ... -  《MOLECULAR CANCER THERAPEUTICS》

Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency.

Ceccon M ，Merlo MEB ，Mologni L ，Poggio T ，Varesio LM ，Menotti M ，Bombelli S ，Rigolio R ，Manazza AD ，Di Giacomo F ，Ambrogio C ，Giudici G ，Casati C ，Mastini C ，Compagno M ，Turner SD ，Gambacorti-Passerini C ，Chiarle R ，Voena C ... -  《-》

ALK kinase domain mutations in primary anaplastic large cell lymphoma: consequences on NPM-ALK activity and sensitivity to tyrosine kinase inhibitors.

Lovisa F ，Cozza G ，Cristiani A ，Cuzzolin A ，Albiero A ，Mussolin L ，Pillon M ，Moro S ，Basso G ，Rosolen A ，Bonvini P ... -  《PLoS One》

Alpha-tocopherol attenuates the anti-tumor activity of crizotinib against cells transformed by NPM-ALK.

Uchihara Y ，Ueda F ，Tago K ，Nakazawa Y ，Ohe T ，Mashino T ，Yokota S ，Kasahara T ，Tamura H ，Funakoshi-Tago M ... -  《PLoS One》