Rotating between ponatinib and imatinib temporarily increases the efficacy of imatinib as shown in a chronic myeloid leukaemia model

Abstract

Targeted therapies for chronic myeloid leukaemia (CML) are effective, but rarely curative. Patients typically require treatment indefinitely, which gives ample time for drug resistance to evolve. Drug resistance issues are one of the main causes of death owing to CML, thus any means of preventing resistance are of importance. Drug rotations, wherein treatment is switched periodically between different drugs are one such option, and have been theorized to delay the onset of resistance. In vitro testing of drug rotation therapy is a first step towards applying it in animal or human trials. We developed a method for testing drug rotation protocols in CML cell lines based around culturing cells with a moderate amount of inhibitors interspersed with washing procedures and drug swaps. Drug rotations of imatinib and ponatinib were evaluated in a CML specific cell line, KCL-22. The growth of KCL-22 cells was initially reduced by a drug rotation, but the cells eventually adapted to the protocol. Our results show that ponatinib in a drug rotation temporarily sensitizes the cells to imatinib, but the effect is short-lived and is eventually lost after a few treatment cycles. Possible explanations for this observation are discussed.

Allosteric regulation of autoinhibition and activation of c-Abl

“…They compete with the nucleotide, adenosine triphosphate (ATP), at the ATP-binding pocket of the kinase domain. Unfortunately, their efficacies are affected in patients harboring point mutations, especially the gatekeeper T315I (numbered in Abl 1b) mutation [24] , [25] , [26] . The disease can relapse or be refractory in some patients who have already received the TKIs.…”

“…Phase 2 clinical trials was stopped due to its adverse effect on the patients’ arteries [27] . A temporary drug switching with imatinib was proposed [26] . Recently, an allosteric inhibitor of Bcr-Abl, asciminib (ABL001), was clinically demonstrated to have high inhibition potency, including of Bcr-Abl mutants with the T315I alteration, and was approved by the U.S. Food and Drug Administration (FDA) for the treatment of CML [29] .…”

How to improve treatment‐free remission eligibility in chronic myeloid leukaemia?

“…58 A study involving CML-specific KCL-22 cell cultures evaluated a drug rotation protocol with imatinib and ponatinib. 59 Initially, the growth of KCL-22 cells was reduced by the drug rotation, although the cells eventually adapted to the protocol, showing a temporary sensitization to imatinib, albeit of short duration after several treatment cycles. Nevertheless, the authors find it beneficial to initiate treatment with a TKI less prone to drug resistance, such as ponatinib, followed by subsequent treatment with a more sensitive one that has fewer side effects.…”

“…A study involving CML‐specific KCL‐22 cell cultures evaluated a drug rotation protocol with imatinib and ponatinib 59 . Initially, the growth of KCL‐22 cells was reduced by the drug rotation, although the cells eventually adapted to the protocol, showing a temporary sensitization to imatinib, albeit of short duration after several treatment cycles.…”

Higher‐order interactions of Bcr‐Abl can broaden chronic myeloid leukemia (CML) drug repertoire

“…The emergence of imatinib, an orthosteric tyrosine kinase inhibitor (TKI) occupying the APT‐binding pocket in the inactive state of the Abl kinase domain, and weakening its phosphorylation ability (Astl & Verkhivker, 2019 ; Lindström & Friedman, 2022 ; Liu, Zhang, et al, 2022 ; Verkhivker, 2021 ; Yeung et al, 2021 ), has proven a revolutionary advance in the therapy of Bcr‐Abl‐associated leukemia. Most patients who were administered imatinib have had a lifespan indistinguishable from healthy people (Kantarjian & Cortes, 2014 ).…”