Acute myeloid leukemia drug resistance: targetable nodes and the clinical trajectory of small-molecule inhibitors.

ABSTRACT: Acute myeloid leukemia (AML) is paradigmatic for therapeutic resistance driven by genetic heterogeneity, epigenetic plasticity and microenvironmental protection. Over the past decade, six targeted or pathway-directed small molecules-midostaurin, gilteritinib, quizartinib, ivosidenib, enasidenib, venetoclax and glasdegib-have changed frontline and relapsed/refractory (R/R) practice in genomically defined subgroups or in patients unfit for intensive chemotherapy. Yet primary refractoriness and early relapse remain common, frequently via adaptive rewiring of apoptotic dependencies, clonal evolution and differentiation resistance. Here we integrate mechanistic insights with clinical evidence to: (i) map resistance biology onto targetable nodes (apoptosis control; signalling kinases; chr

SUBMITTER: Zhang X 

PROVIDER: S-EPMC12672468 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature