Abstract 663: Targeting autophagy potentiates the anti-tumoral action of crizotinib in ALK-positive anaplastic large cell lymphoma

ALK (Anaplastic Lymphoma Kinase)-positive Anaplastic Large Cell Lymphoma (ALCL) occurs predominantly in children and young adults. Their chemotherapeutic treatment leads to a 5-year overall survival amounted to 70-80%. The tumor relapses are often very aggressive and lethal and their underlying mechanisms are unknown. Therefore, there is still a need to improve current therapy. Crizotinib is the most advanced ALK tyrosine kinase inhibitor already used in clinics for ALK-associated lung cancers. However, mechanisms of escape to crizotinib have been reported in cell lines and patients submitted to continuous crizotinib treatment. Thus, its use in frontline treatment for ALCL is hampered by the emergence of resistance. As autophagy has been proposed as a cell survival mechanism potentially involved in the acquisition of resistance to tyrosine kinase inhibitor, we investigated here whether autophagy was activated during ALCL treatment. We demonstrated in ALCL that autophagy is induced upon ALK inactivation, as a pro-survival response. We found that different ALK inhibition approaches (crizotinib or ALK-targeting siRNA) combined with autophagy inhibition (chloroquine, 3-methyladenine or ATG7-targeting siRNA) compromised cell survival and cell growth. Altogether, our results suggest that crizotinib and chloroquine (two drugs already used in clinics) co-treatment could be beneficial for ALK-positive ALCL patients. Citation Format: Geraldine MITOU, Julie FRENTZEL, Laurence LAMANT, Fabienne MEGGETTO, Estelle ESPINOS, Patrice CODOGNO, Pierre BROUSSET, Sylvie GIURIATO. Targeting autophagy potentiates the anti-tumoral action of crizotinib in ALK-positive anaplastic large cell lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 663. doi:10.1158/1538-7445.AM2015-663