S126 COMBINATION OF ASCIMINIB (ABL001) WITH ATP‐COMPETITIVE TYROSINE KINASE INHIBITORS TARGETS EARLY CML PROGENITOR CELLS. Article Swipe

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Chinmay Munje , R. Katherine Hyde , Ross Kinstrie , Rebecca Mitchell , Mary T. Scott , Vignir Helgason , Heather G. Jørgensen , David Vetrie , Mhairi Copland · YOU? · · 2019 · Open Access · · DOI: https://doi.org/10.1097/01.hs9.0000558724.47364.8c

Background: The BCR‐ABL1 chimeric oncoprotein drives chronic myeloid leukaemia (CML) pathogenesis. The introduction of tyrosine kinase inhibitors (TKIs) has transformed clinical outcomes for patients with CML, with over 80% of those treated with imatinib (IM) surviving for more than 10 years. Second and third‐generation TKIs are more potent and can impede the emergence of resistance, inducing deep molecular responses in both untreated and IM‐resistant CML patients. Despite the success of TKIs, up to 35% of patients discontinue their TKI due to intolerance or develop resistance and this remains a key area of unmet clinical need. Asciminib (formerly ABL001) is a potent and selective allosteric inhibitor of ABL1 that binds to the myristoyl binding pocket of ABL1 to hold BCR‐ABL1 in an inactive conformation. Preclinical studies have shown that asciminib selectively inhibits the growth of BCR‐ABL1 positive (+) cells regardless of the presence of BCR‐ABL1 point mutations 1 . Clinical trials for patients with CML or Ph+ acute lymphoblastic leukaemia, testing asciminib alone and in combination with TKIs are currently underway and preliminary results are promising. Aims: To assess if dual inhibition of BCR‐ABL1 leads to improved treatment outcomes in preclinical studies. Methods: Here, we assess the effects of asciminib, alone and in combination with ATP‐competitive TKIs (IM, nilotinib (NIL) and ponatinib (PON)) in CML cell lines and primary CD34+ chronic phase (CP)‐CML stem/progenitor cells (HSPC). We assessed synergy using resazurin readouts using CompuSyn Software. We performed cell counts, apoptosis, cell‐cycle and proliferation assays to determine the effect of drug combinations in CML cell lines and primary samples; and confirmed effects on primitive cells using colony‐forming cell (CFC) and long‐term culture‐initiating cell (LTC‐IC) assays in vitro . Results: Dose‐response studies using the resazurin assays in CML cell lines (Bv173, K562, KCL22) indicate that asciminib is potent at low nanomolar concentration, even in cells that express the BCR‐ABL1 T315I point mutation (KCL22). Apoptosis and cell cycle assays’ assessed by FACS showed that the inhibitory effects of asciminib were maintained in KCL22 T315I ‐expressing cells when asciminib was used in combination with PON. Washout studies with asciminib in KCL22 WT/T315I ‐expressing cells demonstrated a prolonged phenotypic response using low‐nanomolar doses of asciminib as the cells failed to regrow and had irreversible cell‐cycle damage. Primary CD34+ CML HSPCs demonstrated proliferation arrest and increased apoptosis (70–100% increase relative to control; p < 0.001) when treated for up to 72 hours with asciminib, alone and in combination with IM or NIL. LTC‐IC and CFC assays, determining the functional activity of primitive CML HSPCs in vitro, demonstrated that the combination of asciminib with IM or NIL reduced colony outputs (60–90% decrease relative to controll, p < 0.001 ) , beyond that achieved with each drug alone (40–80% relative to control, p < 0.001 ) , and in separate experiments, with minimal effect on normal HSPC. Summary/Conclusion: These results suggest that asciminib represents a novel therapeutic approach with effects on primitive CP‐CML HSPCs both as a single agent and in combination with TKI and has efficacy in cells expressing the multi‐TKI resistant T315I mutation. We are now investigating the mechanism of action for asciminib, alone and in combination with NIL, by RNA‐sequencing.

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article

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en

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https://doi.org/10.1097/01.hs9.0000558724.47364.8c

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gold

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https://openalex.org/W2949253837

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https://doi.org/10.1097/01.hs9.0000558724.47364.8c

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Title

S126 COMBINATION OF ASCIMINIB (ABL001) WITH ATP‐COMPETITIVE TYROSINE KINASE INHIBITORS TARGETS EARLY CML PROGENITOR CELLS.

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article

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en

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2019

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2019-06-01

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Chinmay Munje, R. Katherine Hyde, Ross Kinstrie, Rebecca Mitchell, Mary T. Scott, Vignir Helgason, Heather G. Jørgensen, David Vetrie, Mhairi Copland

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https://doi.org/10.1097/01.hs9.0000558724.47364.8c

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gold

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https://doi.org/10.1097/01.hs9.0000558724.47364.8c

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Nilotinib, Tyrosine kinase, Progenitor cell, Cancer research, Medicine, Imatinib, Dasatinib, Ponatinib, Pharmacology, Myeloid leukemia, Stem cell, Immunology, Biology, Internal medicine, Cell biology, Receptor

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