Intrinsic cellular resistance to BCR::ABL1 inhibitors.

The clinical implementation of BCR::ABL1 tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) represents one of the big successes of mechanism-based cancer therapy. In 2025, survival of patients who start TKI therapy while in the chronic phase is approaching that of age-matched controls. Despite this paradigm shift, significant challenges remain. Some patients still develop overt TKI resistance and progress to bast phase, and the majority continue to harbor residual leukemia and require life-long TKI therapy. Growth and survival signals arising from the microenvironment or from within the leukemia cells confer various degrees of resistance to support a spectrum of leukemic activity ranging from overt acute leukemia in blast phase to persistence of minimal residual disease in patients with a deep molecular response. Here we review cell-intrinsic resistance, covering both reactivation of BCR::ABL1 kinase activity and the less welldefined mechanisms underlying BCR::ABL1-independent TKI resistance. We propose that the pathways used by CML to escape TKI effects reflect the potential and the constraints of BCR::ABL1- driven reprogramming of hematopoietic stem and progenitor cells and that the role of BCR::ABL1 functions other than kinase activity may be underappreciated, providing a rationale for the clinical development of BCR::ABL1 degraders.