Targeting of HSP70/HSF1 Axis Abrogates In Vitro Ibrutinib-Resistance in Chronic Lymphocytic Leukemia

SIMPLE SUMMARY: The use of ibrutinib has changed the management and clinical history of patients with multiple-treated chronic lymphocytic leukemia (CLL). Nevertheless, an increasing number of patients develop resistance to treatment, with mechanisms still to be fully clarified. Since HSP70 plays a pivotal role in mediating the survival and the progression of CLL, we herein addressed the role of HSP70 and its regulator HSF1 in the development of ibrutinib-mediated resistance. We found an increase in both proteins when the treatment was failing, and thus the disease was progressing. This suggests the involvement of HSP70 in mechanisms of drug resistance. Moreover, we demonstrated that the use, at different levels, of HSP70/HSF1 axis inhibitors could represent a novel rational therapeutic approach to overcome ibrutinib resistance in those patients who relapsed after this type of treatment. ABSTRACT: The Btk inhibitor ibrutinib has significantly changed the management of chronic lymphocytic leukemia (CLL) patients. Despite its clinical efficacy, relapses occur, and outcomes after ibrutinib failure are poor. Although BTK and PLCγ2 mutations have been found to be associated with ibrutinib resistance in a fair percentage of CLL patients, no information on resistance mechanisms is available in patients lacking these mutations. The heat shock protein of 70 kDa (HSP70) and its transcription factor heat shock factor 1 (HSF1) play a role in mediating the survival and progression of CLL, as well as taking part in drug resistance in various cancers. We demonstrated that resveratrol and related phenols were able to induce apoptosis in vitro in leukemic cells from CLL untreated patients by acting on the HSP70/HSF1 axis. The same was achieved in cells recovered from 13 CLL patients failing in vivo ibrutinib treatment. HSP70 and HSF1 levels decreased following in vitro treatment, correlating to apoptosis induction. We suggest an involvement of HSP70/HSF1 axis in controlling resistance to ibrutinib in CLL cells, since their inhibition is effective in inducing in vitro apoptosis in cells from ibrutinib refractory patients. The targeting of HSP70/HSF1 axis could represent a novel rational therapeutic strategy for CLL, also for relapsing patients.