PP2A Inhibitor LB100 Enhances the Sensitivity of NPM-ALK+ALCL to Crizotinib and Reverses the Resistance of ALCL to Crizotinib

Anaplastic large cell lymphoma (ALCL) is a rare and aggressive non-Hodgkin's lymphoma commonly discovered in children and adolescents. Despite the high remission rates in ALCL achieved by conventional chemotherapy based on conventional CHOP (cyclophosphamide, adriamycin, vincristine, prednisone), relapse and drug resistance occur in more than 40% of patients. The clinical use of the ALK inhibitor crizotinib in most relapsed refractory NPM-ALK+ ALCL in recent years has demonstrated effective treatment, but crizotinib resistance and intolerance due to the corresponding side effects still occur in 30% of cases. This urgently requires us to find new treatments to enhance the sensitivity of crizotinib as well as to overcome the resistance of crizotinib in ALCL. PP2A has been considered a tumor suppressor gene in the past, but with better understanding, it is two-sided, playing different roles in various types of tumors. In addition, it has been found that PP2A is closely related to drug sensitivity and resistance. LB100, a novel water-soluble PP2A inhibitor, is gaining attention because of its significantly higher safety profile than traditional PP2A inhibitors. It has potent effects on tumor inhibition and could increase tumor sensitivity to radiotherapy. In this study, we first established a crizotinib-resistant NPM-ALK+ ALCL cell model by exposing a highly sensitive NPM-ALK-positive ALCL cell line to continuously increasing doses of crizotinib until resistance developed. The PP2A inhibitor LB100 was then applied to normal and resistant cell lines to explore changes in their biological activity. We found that LB100 significantly inhibited the viability of normal and drug-resistant ALCL cell lines and was more sensitive in drug-resistant lines. In addition, a combination of LB100 and crizotinib was applied in normal and resistant cell lines to analyze the effect of LB100 on sensitization to crizotinib and reversal of drug resistance. LB100 significantly enhanced the killing effect of crizotinib in normal tumor cell lines and partially reverses crizotinib resistance in resistant lines. Western blot and immunofluorescence showed that LB100 leads to increased cellular G1 phase block by increasing cellular DNA damage, which in turn enhances the sensitivity of crizotinib. The above experiments showed that LB100, as an effective inhibitor of PP2A, can significantly increase the effect of crizotinib against normal NPM-ALK+ ALCL, inhibit the growth of crizotinib-resistant strains, and partially restore the sensitivity of crizotinib, which is expected to be a new therapeutic tool for ALCL. In addition, simultaneous targeting of PP2A and ALK has a very high potential in overcoming ALK inhibitor resistance in ALCL and could be a new therapeutic strategy to overcome drug resistance.

No relevant conflicts of interest to declare.