Mechanisms of Resistance and Implications for Treatment Strategies in Chronic Myeloid Leukaemia

SIMPLE SUMMARY: Chronic myeloid leukaemia (CML) is a type of blood cancer that is currently well-managed with drugs that target cancer-causing proteins. However, a significant proportion of CML patients do not respond to those drug treatments or relapse when they stop those drugs because the cancer cells in those patients stop relying on that protein and instead develop a new way to survive. Therefore, new treatment strategies may be necessary for those patients. In this review, we discuss those additional survival pathways and outline combination treatment strategies to increase responses and clinical outcomes, improving the lives of CML patients. ABSTRACT: Tyrosine kinase inhibitors (TKIs) have revolutionised the management of chronic myeloid leukaemia (CML), with the disease now having a five-year survival rate over 80%. The primary focus in the treatment of CML has been on improving the specificity and potency of TKIs to inhibit the activation of the BCR::ABL1 kinase and/or overcoming resistance driven by mutations in the BCR::ABL1 oncogene. However, this approach may be limited in a significant proportion of patients who develop TKI resistance despite the effective inhibition of BCR::ABL1. These patients may require novel therapeutic strategies that target both BCR::ABL1-dependent and BCR::ABL1-independent mechanisms of resistance. The combination treatment strategies that target alternative survival signalling, which may contribute towards BCR::ABL1-independent resistance, could be a successful strategy for eradicating residual leukaemic cells and consequently increasing the response rate in CML patients.