Antitumor efficacy of arsenic/interferon in preclinical models of chronic myeloid leukemia resistant to tyrosine kinase inhibitors

Abstract

Background Tyrosine kinase inhibitors (TKIs) are the standard treatment for chronic myeloid leukemia (CML). Despite their clinical success, TKIs are faced with challenges such as treatment resistance, which may be driven by kinase domain mutations, and frequent disease relapse upon the cessation of treatment. The combination of arsenic trioxide (ATO) and interferon‐α (IFN) was previously demonstrated to inhibit proliferation and induce apoptosis in CML cell lines, prolong the survival of primary wild‐type CML mice, and dramatically decrease the activity of leukemia‐initiating cells (LICs). Methods The ATO/IFN combination was tested in vitro on imatinib (IMN)‐resistant K562‐R and Ar230‐R cells. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick‐end labeling assays were used to evaluate proliferation and apoptosis, respectively. The acridine orange assay was used to assess autophagy, and quantitative reverse transcription–polymerase chain reaction was used to assess the involvement of the hedgehog (Hh) pathway. In vivo, a retroviral transduction/transplantation T315I BCR‐ABL CML mouse model was used to assay the effect of the treatment on survival, tumor burden (histopathology and blood counts), and LIC activity (secondary transplantation). Results In vitro, ATO/IFN synergized to inhibit proliferation and induce apoptosis of IMN‐resistant cells with variant modes of resistance. Furthermore, the preclinical effects of ATO/IFN were associated with induction of autophagy along with inhibition of the Hh pathway. Most remarkably, ATO/IFN significantly prolonged the survival of primary T315I‐CML mice and displayed a dramatic impairment of disease engraftment in secondary mice, which reflected decreased LIC activity. Conclusions Collectively, the ATO/IFN strategy has been demonstrated to have the potential to lead to durable remissions in TKI‐resistant CML preclinical models and to overcome various TKI‐specific mechanisms of resistance.

PKC‐β/Alox5 axis activation promotes Bcr‐Abl‐independent TKI‐resistance in chronic myeloid leukemia

“…Resistance to TKI in CML can lead to disease progression and relapse, especially in advanced stage (El Eit et al, 2019;Sundaram et al, 2019). The mechanism can be broadly classified as either Bcr-Abl-dependent or independent according to if the kinase domain was mutant or not (Ma et al, 2014;Mitchell et al, 2018).…”

Second-Generation Tyrosine Kinase Inhibitor Discontinuation in Chronic Myeloid Leukemia Patients with Stable Deep Molecular Response: A Systematic Review and a Meta-Analysis

“…This complies with the results of the study by Chen et al on discontinuation of first- and second-generation TKIs [ 34 ]. El Eit et al's experimental studies on CML mouse models concluded that IFN may allow TML-resistant CML mice to overcome various TKI-specific resistance mechanisms and achieve durable remission [ 35 ]. This is probably because the dormant state may be the vital mechanism observed for normal HSCs and leukemia stem cells (LSCs) to resist proliferative chemical resistance [ 36 ].…”

Improving outcomes in chronic myeloid leukemia through harnessing the immunological landscape

“…The authors suggested that the principal mechanism underlying this success was biphasic—with immune activation induced by dasatinib pre-treatment followed by restoration of immunological surveillance after application of IFN-α therapy [ 91 ]. In vitro, IFN-α combined with arsenic trioxide, synergized to inhibit proliferation and induce apoptosis of imatinib-resistant CML cell lines, whilst in vivo murine models showed significantly prolonged survival of primary T315I-CML mice whilst dramatically impairing disease engraftment in secondary mice [ 92 ]. IFN-α may thus provide an alternative therapeutic approach in selected TKI-resistant mutation positive CML patients, particularly those ineligible for alternative options such as BM transplantation.…”