Efficacy of a combination of TKI and a novel allosteric inhibitor asciminib in chronic myeloid leukaemia

Chronic Myeloid Leukemia smear

Chronic Myeloid Leukemia smear
Paulo Henrique Orlandi Mourao  (CC BY-SA 3.0)

Clinical trials for the treatment of Chronic Myeloid Leukemia (CML) are currently underway using asciminib (ABL001).

The trials are using this allosteric inhibitor alone, and in combination with ATP-competitive tyrosine kinase inhibitors (TKIs: imatinib, nilotinib or dasatinib), to inhibit the constitutively active tyrosine kinase Bcr-Abl.

We will then examine mechanisms of treatment resistance in vitro, in an attempt to predict emergent disease resistance mechanisms that may arise.

The aims of this project are: 

  1. Investigation of the synergistic effect of the combination of TKI and asciminib. 
  2. Understand the signalling pathway changes in BCR-ABL+ cell lines and CML patient cells when combination therapy is given.
  3. Generation of resistant cell lines in the laboratory setting. This provides a useful tool for predicting and studying patient responses in vivo. 

Understanding how these drugs work in synergy will enhance our ability to predict whether patients are likely to respond to combination therapy, and clarify ways to maximise synergism between these agents.

In this project, BCR-ABL1+ cell lines will be exposed long term to gradually increasing concentrations of asciminib in combination with TKI. Mechanisms of resistance will be interrogated during resistance development and once overt resistance is observed.

Professor Tim Hughes

Supervisors

Professor Timothy Hughes

Co-supervisorsDr David Yeung | Dr Liu Lu

Research area: Cancer program - South Australian Health and Medical Research Institute

Recommended honours enrolment: Honours in Molecular and Biomedical Science

Tagged in Honours projects - Molecular and biomedical science, Honours projects - Molecular and biomedical science: Microbiology and immunology, Honours projects - Timothy Hughes, Honours projects - David Yeung, Honours projects - Liu Lu