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Pharmacological difference between degrader and inhibitor against oncogenic BCR-ABL kinase.

ABSTRACT: Chronic myelogenous leukemia (CML) is characterized by the oncogenic fusion protein, BCR-ABL protein kinase, against which clinically useful inhibitors have been developed. An alternative approach to treat CML is to degrade the BCR-ABL protein. Recently, potent degraders against BCR-ABL have been developed by conjugating dasatinib to ligands for E3 ubiquitin ligases. Since the degraders contain the dasatinib moiety, they also inhibit BCR-ABL kinase activity, which complicates our understanding of the impact of BCR-ABL degradation by degraders in CML growth inhibition. To address this issue, we chose DAS-IAP, as a potent BCR-ABL degrader, and developed a structurally related inactive degrader, DAS-meIAP, which inhibits kinase activity but does not degrade the BCR-ABL protein. DAS-IAP showed slightly weaker activity than DAS-meIAP in inhibiting cell growth when CML cells were treated for 48?h. However, DAS-IAP showed sustained growth inhibition even when the drug was removed after short-term treatment, whereas CML cell growth rapidly resumed following removal of DAS-meIAP and dasatinib. Consistently, suppression of BCR-ABL levels and downstream kinase signaling were maintained after DAS-IAP removal, whereas kinase signaling rapidly recovered following removal of DAS-meIAP and dasatinib. These results indicate that BCR-ABL degrader shows more sustained inhibition of CML cell growth than ABL kinase inhibitor.

SUBMITTER: Shibata N

PROVIDER: S-EPMC6131351 | biostudies-other | 2018 Sep

REPOSITORIES: biostudies-other

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Pharmacological difference between degrader and inhibitor against oncogenic BCR-ABL kinase.

Shibata Norihito N Shimokawa Kenichiro K Nagai Katsunori K Ohoka Nobumichi N Hattori Takayuki T Miyamoto Naoki N Ujikawa Osamu O Sameshima Tomoya T Nara Hiroshi H Cho Nobuo N Naito Mikihiko M

Scientific reports 20180910 1

Chronic myelogenous leukemia (CML) is characterized by the oncogenic fusion protein, BCR-ABL protein kinase, against which clinically useful inhibitors have been developed. An alternative approach to treat CML is to degrade the BCR-ABL protein. Recently, potent degraders against BCR-ABL have been developed by conjugating dasatinib to ligands for E3 ubiquitin ligases. Since the degraders contain the dasatinib moiety, they also inhibit BCR-ABL kinase activity, which complicates our understanding o ...[more]

PMID: 30202081

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Project description:Previously, it has been stated that the BCR-ABL fusion-protein is sufficient to induce Chronic Myeloid Leukemia (CML), but additional genomic-changes are required for disease progression. Hence, we profiled control and tyrosine kinase inhibitors (TKI) alone or in combination with other drug-treated CML-samples in different phases, categorized as drug-sensitive and drug-resistant on the basis of BCR-ABL transcripts, the marker of major molecular-response. Molecular-profiling was done using the molecular-inversion probe-based-array, Human Transcriptomics-Array2.0, and Axiom-Biobank genotyping-arrays. At the transcript-level, clusters of control, TKI-resistant and TKI-sensitive cases were correlated with BCR-ABL transcript-levels. Both at the gene- and exon-levels, up-regulation of MPO, TPX2, and TYMS and down-regulation of STAT6, FOS, TGFBR2, and ITK lead up-regulation of the cell-cycle, DNA-replication, DNA-repair pathways and down-regulation of the immune-system, chemokine- and interleukin-signaling, TCR, TGF beta and MAPK signaling pathways. A comparison between TKI-sensitive and TKI-resistant cases revealed up-regulation of LAPTM4B, HLTF, PIEZO2, CFH, CD109, ANGPT1 in CML-resistant cases, leading to up-regulation of autophagy-, protein-ubiquitination-, stem-cell-, complement-, TGFβ- and homeostasis-pathways with specific involvement of the Tie2 and Basigin signaling-pathway. Dysregulated pathways were accompanied with low CNVs in CP-new and CP-UT-TKI-sensitive-cases with undetectable BCR-ABL-copies. High CNVs (previously reported gain of 9q34) were observed in BCR-ABL-independent and -dependent TKI, non-sensitive-CP-UT/AP-UT/B-UT and B-new samples. Further, genotyping CML-CP-UT cases with BCR-ABL 0-to-77.02%-copies, the identified, rsID239798 and rsID9475077, were associated with FAM83B, a candidate for therapeutic resistance. The presence of BCR-ABL, additional genetic-events, dysregulated-signaling-pathways and rsIDs associated with FAM83B in TKI-resistant-cases can be used to develop a signature-profile that may help in monitoring therapy.

Project description:BACKGROUND: Point mutations of the BCR-ABL tyrosine kinase domain are considered the predominant cause of imatinib resistance in chronic myeloid leukemia. The expansion of mutant BCR-ABL-positive clones under selective pressure of tyrosine kinase inhibition is referred to as clonal selection; there are few data on the reversibility of this phenomenon. DESIGN AND METHODS: The changes of expression of mutant BCR-ABL-positive alleles after cessation of tyrosine kinase inhibitor treatment were examined in 19 patients with chronic myeloid leukemia harboring different mutations in a longitudinal follow-up. The proportion of mutant alleles was quantified by amplification of rearranged ABL sequences followed by mutation-specific restriction digestion, electrophoresis and densitometry. The size of mutant clones was established as a measure of the absolute amount of mutant cells considering the proportion of mutant BCR-ABL transcripts and the total level of BCR-ABL obtained by quantitative reverse transcriptase polymerase chain reaction. RESULTS: The median proportion of mutant transcripts was 97% before and 8% after cessation of tyrosine kinase inhibitor treatment indicating a relative decline of 88% within a median of 6 months. The relative decrease in the size of the mutant clones was 86%. Repeated selection and deselection of the mutant clone after resumption and second cessation of tyrosine kinase inhibitor treatment was observed in individual patients. CONCLUSIONS: Deselection of mutant BCR-ABL-positive clones after cessation of tyrosine kinase inhibitor treatment might be a common, rapid and reproducible phenomenon, although some patients harboring the T315I mutation showed no deselection. Cessation of tyrosine kinase inhibitor treatment may lead to the regression of T315I mutant clones to a level under the limit of detection, offering the therapeutic option of resumed tyrosine kinase inhibitor treatment under close surveillance of the mutation status.

Dataset Information

Pharmacological difference between degrader and inhibitor against oncogenic BCR-ABL kinase.

Publications

Pharmacological difference between degrader and inhibitor against oncogenic BCR-ABL kinase.

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