Targeting of HSP70/HSF1 Axis Abrogates In Vitro Ibrutinib-Resistance in Chronic Lymphocytic Leukemia - PubMed
Source : https://pubmed.ncbi.nlm.nih.gov/34771616/
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 resistan ...
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.
• Source: Cancers
• Conclusion/Relevance: “In several tumors, HSP70 and HSF1 overexpression is one of the causes of low therapy response, allowing cancer cells to escape apoptosis and survive despite stressing conditions. Our findings suggest an involvement of HSP70/HSF1 axis in controlling pharmacological resistance to ibrutinib in CLL cells, since their inhibition is effective in inducing in vitro apoptosis in cells from ibrutinib refractory patients. For this reason, the use of HSP70 and HSF1 inhibitors could represent a novel approach (alone or in combination) to overcome ibrutinib resistance in those patients who relapsed after this type of treatment; moreover, these proteins could be used as a marker to find early relapse in patients. Considering the role played by ibrutinib in the management of different non-Hodgkin Lymphomas (i.e., MZL, MCL, DLBCL, WM), HSP70/HSF1 axis inhibition would be of clinical relevance not only in CLL, but also in other B-lymphoproliferative diseases.”
• A growing number of patients develop resistance to treatment with ibrutinib. Underlying mechanisms need to be elucidated. Notably, HSP70 is of chief importance in mediating the progression of CLL.
• The investigators found that the proteins HSP70 and its regulator HSF1 played a role in ibrutinib-mediated resistance, and levels of both proteins increased in the case of treatment failure, as well as disease progression. They therefore hypothesized that HSP70 was involved in drug resistance.