Abstract
ALK-positive Anaplastic Large Cell Lymphoma (ALCL) represents a subset of Non-Hodgkin Lymphoma whose treatment benefited from crizotinib development, a dual ALK/MET inhibitor. Crizotinib blocks ALK-triggered pathways such as PI3K/AKT/mTOR, indispensable for survival of ALK-driven tumors.Despite the positive impact of targeted treatment in ALCL, resistant clones are often selected during therapy. Strategies to overcome resistance include the design of second generation drugs and the use of combined therapies that simultaneously target multiple nodes essential for cells survival. We investigated the effects of combined ALK/mTOR inhibition. We observed a specific synergistic effect of combining ALK inhibitors with an mTOR inhibitor (temsirolimus), in ALK+ lymphoma cells. The positive cooperation resulted in an increased inhibition of mTOR effectors, compared to single treatments, a block in G0/G1 phase and induction of apoptosis. The combination was able to prevent the selection of resistant clones, while long-term exposure to single agents led to the establishment of resistant cell lines, with either ALK inhibitor or temsirolimus. In vivo, mice injected with Karpas 299 cells and treated with low dose combination showed complete regression of tumors, while only partial inhibition was obtained in single agents-treated mice. Upon treatment stop the combination was able to significantly delay tumor relapses. Re-challenge of relapsed tumors at a higher dose led to full regression of xenografts in the combination group, but not in mice treated with lorlatinib alone. In conclusion, our data suggest that the combination of ALK and mTOR inhibitors could be a valuable therapeutic option for ALK+ ALCL patients.
Highlights
Rational combined therapy has been widely investigated in recent years as a strategy to increase the efficacy of targeted therapy and to prevent/overcome resistance, with several examples of positive cooperation between two drugs [1,2,3,4].ALK+ Anaplastic Large Cell Lymphomas (ALCL) represent a defined subset of Non-Hodgkin lymphomas (NHL) characterized by chromosomal rearrangements involving the Anaplastic Lymphoma Kinase (ALK) [5]
ALK positive ALCL therapy has benefited from crizotinib development, the first ALK inhibitor to be successfully used in patients
Subsequent development of next-generation ALK inhibitors such as alectinib and lorlatinib was aimed to improve the efficacy and overcome the resistance observed in a significant fraction of patients treated with crizotinib
Summary
Rational combined therapy has been widely investigated in recent years as a strategy to increase the efficacy of targeted therapy and to prevent/overcome resistance, with several examples of positive cooperation between two drugs [1,2,3,4].ALK+ Anaplastic Large Cell Lymphomas (ALCL) represent a defined subset of Non-Hodgkin lymphomas (NHL) characterized by chromosomal rearrangements involving the Anaplastic Lymphoma Kinase (ALK) [5]. Crizotinib is the first tyrosine kinase www.impactjournals.com/oncotarget inhibitor (TKI) successfully tested in ALCL patients [8] and in 2011 it was approved for the treatment of ALK+ non-small cell lung cancer (NSCLC) [9,10,11]. Resistance to crizotinib frequently arises, mainly caused by point mutations or bypass mechanisms, causing tumor relapse [12,13,14]. This has spurred the development of second generation TKIs [15,16,17,18,19], including alectinib (CH5424802) and lorlatinib (PF-06463922). Lorlatinib shows significant activity against all crizotinib-resistant ALK mutants and it is currently in phase 1/2 clinical trial in ALK+ and ROS+ NSCLC [21]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call