BCR-ABL1 compound mutants display differential and dose-dependent responses to ponatinib

Byrgazov, Konstantin; Lucini, Chantal; Valent, Peter; Hantschel, Oliver; Lion, Thomas

doi:10.3324/haematol.2017.176347

Cited by 26 publications

(27 citation statements)

References 13 publications

(13 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The great majority of CMs have been predicted to display resistance to imatinib and all second-generation TKIs [113]. As far as ponatinib is concerned, recent in vitro data suggest that individual CMs have differential responses to ponatinib, ranging from sensitive to highly resistant [114]. Interestingly, CMs including the T315I or F317L revealed a particularly high resistance to ponatinib, whereas several other CMs conferred an intermediate level of resistance which could be overcome by employing the appropriate dose of the kinase inhibitor [114].…”

Section: Main Textmentioning

confidence: 99%

“…As far as ponatinib is concerned, recent in vitro data suggest that individual CMs have differential responses to ponatinib, ranging from sensitive to highly resistant [114]. Interestingly, CMs including the T315I or F317L revealed a particularly high resistance to ponatinib, whereas several other CMs conferred an intermediate level of resistance which could be overcome by employing the appropriate dose of the kinase inhibitor [114]. This consideration may be of importance in view of the current tendency to reduce the dose of ponatinib in order to prevent the occurrence of severe side effects.…”

Section: Main Textmentioning

confidence: 99%

See 1 more Smart Citation

Treatment and monitoring of Philadelphia chromosome-positive leukemia patients: recent advances and remaining challenges

2019

Self Cite

View full text Add to dashboard Cite

The Philadelphia (Ph) chromosome, resulting from the t(9;22)(q34;q11) translocation, can be found in chronic myeloid leukemia (CML) as well as in a subset of acute lymphoblastic leukemias (ALL). The deregulated BCR-ABL1 tyrosine kinase encoded by the fusion gene resulting from the translocation is considered the pathogenetic driver and can be therapeutically targeted. In both CML and Ph-positive (Ph+) ALL, tyrosine kinase inhibitors (TKIs) have significantly improved outcomes. In the TKI era, testing for BCR-ABL1 transcript levels by real-time quantitative polymerase chain reaction (RQ-PCR) has become the gold standard to monitor patient response, anticipate relapse, and guide therapeutic decisions. In CML, key molecular response milestones have been defined that draw the ideal trajectory towards optimal long-term outcomes. Treatment discontinuation (treatment-free remission, TFR) has proven feasible in a proportion of patients, and clinical efforts are now focused on how to increase this proportion and how to best select TFR candidates. In Ph+ ALL, results of trials with second- and third-generation TKIs are challenging the role of intensive chemotherapy and even that of allogeneic stem cell transplantation. Additional weapons are offered by the recently introduced monoclonal antibodies. In patients harboring mutations in the BCR-ABL1 kinase domain, prompt therapeutic reassessment and individualization based on mutation status are important to regain response and prevent disease progression. Next-generation sequencing is likely to become a precious tool for mutation testing because of the greater sensitivity and the possibility to discriminate between compound and polyclonal mutations. In this review, we discuss the latest advances in treatment and monitoring of CML and Ph+ ALL and the issues that still need to be addressed to make the best use of the therapeutic armamentarium and molecular testing technologies currently at our disposal.

show abstract

Section: Main Textmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

Treatment and monitoring of Philadelphia chromosome-positive leukemia patients: recent advances and remaining challenges

2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recent data suggest, however, that only certain compound mutations provide insurmountable resistance to this TKI. These include particularly CMs including the gatekeeper mutation T315I or the adjacent mutation F317L . Such mutations would require concentrations of ponatinib that are not achievable in the clinical setting, even when using the highest possible dosage of 45 mg/day.…”

Section: Screening and Monitoring Of \Bcr‐abl1 Kinase Domain Mutationmentioning

confidence: 99%

“…By contrast, a number of other compound mutations may be controlled by any dose of ponatinib down to 15 mg/day. Some compound mutations, however, display intermediate levels of resistance that can only be controlled by higher doses of ponatinib . This consideration is important because the serious side effects associated with ponatinib treatment appear to be dose‐related, thus leading to the general tendency of limiting the daily dose of this compound.…”

Section: Screening and Monitoring Of \Bcr‐abl1 Kinase Domain Mutationmentioning

confidence: 99%

“…Hence, recent data suggest that the clinical use of mutation testing by NGS goes beyond the selection of an appropriate TKI and response monitoring of individual mutant subclones to TKI treatment in vivo. In some instances, identification of specific mutations may also guide appropriate dosing of the selected TKI …”

Section: Screening and Monitoring Of \Bcr‐abl1 Kinase Domain Mutationmentioning

confidence: 99%

See 1 more Smart Citation

Precision immunotherapy, mutational landscape, and emerging tools to optimize clinical outcomes in patients with classical myeloproliferative neoplasms

Mughal

Lion

Abdel‐Wahab

et al. 2018

Hematological Oncology

Self Cite

View full text Add to dashboard Cite

Following the 47th American Society of Hematology Meeting in 2005, the late John Goldman and Tariq Mughal commenced a conference, the 1st Post-ASH Workshop, which brought together clinicians and scientists, to accelerate the adoption of new therapies for patients with myeloproliferative neoplasms (MPNs). The concept began with recognition of the CML success story following imatinib therapy, the discovery of JAK2 , and the demonstration that BCR-ABL1-negative MPNs are driven by abnormal JAK2 activation. This review is based on the presentations and deliberations at the XIIth Post-ASH Workshop on BCR-ABL1 positive and negative MPNs that took place on December 12 to 13, 2017, in Atlanta, Georgia, immediately following the 59th American Society of Hematology Meeting. We have selected some of the translational research and clinical topics, rather than an account of the proceedings. We discuss the role of immunotherapy in MPNs and the impact of the mutational landscape on TKI treatment in CML. We also consider how we might reduce TKI cardiovascular side effects, the potential role of nutrition as adjunctive nonpharmacologic intervention to reduce chronic inflammation in MPNs, and novel investigational therapies for MPNs.

show abstract

BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph⁺ chronic myeloid leukemia

et al. 2022

Self Cite

View full text Add to dashboard Cite

In most patients with chronic myeloid leukemia (CML) clonal cells can be kept under control by BCR::ABL1 tyrosine kinase inhibitors (TKI). However, overt resistance or intolerance against these TKI may occur. We identified the epigenetic reader BRD4 and its downstream‐effector MYC as growth regulators and therapeutic targets in CML cells. BRD4 and MYC were found to be expressed in primary CML cells, CD34+/CD38− leukemic stem cells (LSC), and in the CML cell lines KU812, K562, KCL22, and KCL22T315I. The BRD4‐targeting drug JQ1 was found to suppress proliferation in KU812 cells and primary leukemic cells in the majority of patients with chronic phase CML. In the blast phase of CML, JQ1 was less effective. However, the BRD4 degrader dBET6 was found to block proliferation and/or survival of primary CML cells in all patients tested, including blast phase CML and CML cells exhibiting the T315I variant of BCR::ABL1. Moreover, dBET6 was found to block MYC expression and to synergize with BCR::ABL1 TKI in inhibiting the proliferation in the JQ1‐resistant cell line K562. Furthermore, BRD4 degradation was found to overcome osteoblast‐induced TKI resistance of CML LSC in a co‐culture system and to block interferon‐gamma‐induced upregulation of the checkpoint antigen PD‐L1 in LSC. Finally, dBET6 was found to suppress the in vitro survival of CML LSC and their engraftment in NSG mice. Together, targeting of BRD4 and MYC through BET degradation sensitizes CML cells against BCR::ABL1 TKI and is a potent approach to overcome multiple forms of drug resistance in CML LSC.

show abstract

BCR-ABL1 compound mutants display differential and dose-dependent responses to ponatinib

Cited by 26 publications

References 13 publications

Treatment and monitoring of Philadelphia chromosome-positive leukemia patients: recent advances and remaining challenges

Treatment and monitoring of Philadelphia chromosome-positive leukemia patients: recent advances and remaining challenges

Precision immunotherapy, mutational landscape, and emerging tools to optimize clinical outcomes in patients with classical myeloproliferative neoplasms

BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph⁺ chronic myeloid leukemia

Contact Info

Product

Resources

About

BCR-ABL1 compound mutants display differential and dose-dependent responses to ponatinib

Cited by 26 publications

References 13 publications

Treatment and monitoring of Philadelphia chromosome-positive leukemia patients: recent advances and remaining challenges

Treatment and monitoring of Philadelphia chromosome-positive leukemia patients: recent advances and remaining challenges

Precision immunotherapy, mutational landscape, and emerging tools to optimize clinical outcomes in patients with classical myeloproliferative neoplasms

BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph+ chronic myeloid leukemia

Contact Info

Product

Resources

About

BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph⁺ chronic myeloid leukemia