BCR-ABL1 COMPOUND MUTANTS DISPLAY DIFFERENTIAL AND DOSE-DEPENDENT RESPONSES TO PONATINIB
Author(s): ,
Konstantin Byrgazov
Affiliations:
Children's Cancer Research Institute,Vienna,Austria
,
Chantal Lucini
Affiliations:
Children's Cancer Research Institute,Vienna,Austria
,
Dieter Printz
Affiliations:
Children's Cancer Research Institute,Vienna,Austria
,
Margit Koenig
Affiliations:
Children's Cancer Research Institute,Vienna,Austria
,
Peter Valent
Affiliations:
Medical University of Vienna,Vienna,Austria
,
Oliver Hantschel
Affiliations:
Swiss Institute for Experimental Cancer Research,Lausanne,Switzerland
Thomas Lion
Affiliations:
Children's Cancer Research Institute,Vienna,Austria
EHA Library. Byrgazov K. Jun 24, 2017; 181883; P596
Dr. Konstantin Byrgazov
Dr. Konstantin Byrgazov
Contributions
Abstract

Abstract: P596

Type: Poster Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 17:30 - 19:00

Location: Poster area (Hall 7)

Background
Despite the dramatic improvement of prognosis in CML patients due to the introduction of tyrosine kinase inhibitors (TKIs), resistance to therapy occurs in a considerable proportion of patients. The best-characterized mechanism of resistance is the acquisition of mutations in the BCR-ABL1 tyrosine kinase domain (TKD) affecting TKI binding. The third-generation TKI ponatinib exerts strong anti-neoplastic effects even in advanced CML stages and is capable of suppressing the kinase activity of BCR-ABL1 carrying any single mutation including T315I. Nevertheless, resistance to ponatinib can evolve in sub-clones carrying BCR-ABL1 variants with two or more mutations on the same allele, if the IC50 values for this TKI exceed the maximum achievable effective plasma levels (efCave). These co-called compound mutations (CMs) are associated with increased oncogenic potential in comparison to individual mutations, and represent a powerful mechanism of potential resistance to all currently available TKIs. The occurrence of compound mutations has been linked particularly to sequential treatment with different TKIs, and the identification of their responsiveness to ponatinib is of paramount importance for the subsequent clinical management.

Aims

1. To determine the spectrum of highly TKI-resistant CMs
2. Measure the responses of BCR-ABL1 CMs to ponatinib

Methods
We have established a BCR-ABL1 protein model facilitating assessment of the presumptive impact of 27 different CMs involving important functional sites of the BCR-ABL1 TKD, and including constellations expected to display high resistance to ponatinib. To assess the anticipated responses to ponatinib in vitro, we have introduced all BCR-ABL1 CMs into Ba/F3 cells using a recently published transposon-mediated approach (Byrgazov et al., Oncotarget 2016, 7(47):78083-78094), and IC50 values of ponatinib were determined.

Results

Most CMs involving sites with no previous evidence for implication in resistance to ponatinib displayed IC50 values below 10 nM. This efCave is readily achievable even with the 15 mg daily dose of ponatinib. CMs revealing elevated resistance to ponatinib in vitro almost invariably included T315I or F317L mutations. While most CMs involving T315I revealed very high IC50 values, some of the predicted compound mutations containing F317L displayed an IC50 for ponatinib in the range of the efCave achievable only with a daily dose of 45 mg. These observations are supported by clinical findings in the PACE trial which revealed impaired responses of patients with CMs involving F317L who had received average daily doses of ponatinib below 45 mg (Deininger et al., Blood 2016, 127(6):703-12).

Conclusion
Current strategies that aim at decreasing the dose of ponatinib to prevent severe side effects should carefully consider the presence and type of mutations in the BCR-ABL1 TKD to enable effective treatment. It would be highly desirable, therefore, to implement testing of the effective plasma drug concentrations and monitoring the kinetics of mutant subclones covering also compound mutations in the routine diagnostic surveillance to provide a basis for optimized clinical management of patients treated with ponatinib.

Session topic: 7. Chronic myeloid leukemia - Biology

Keyword(s): Tyrosine kinase inhibitor, Resistance, BCR-ABL

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