{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T12:39:29Z","timestamp":1792931969681,"version":"4.5.0"},"reference-count":123,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    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\u2014midostaurin, gilteritinib, quizartinib, ivosidenib, enasidenib, venetoclax and glasdegib\u2014have 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\n                    <jats:italic>via<\/jats:italic>\n                    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; chromatin\/lineage programmes; RNA splicing; DNA-damage response; nuclear export; niche adhesion and innate immune evasion); (ii) summarise the clinical trajectory and current limits of approved and emerging small molecules (including menin and LSD1 inhibitors); (iii) propose rules for rational doublets and triplets that are biologically orthogonal yet clinically tolerable; (iv) outline a regulatory timeline for key AML small molecules; and (v) prioritise where drug development should go next, including next-generation BH3 toolkits, clonal-pressure-aware designs, minimal residual disease (MRD)\u2013adapted trials and therapy guided by dynamic functional profiling. The review closes with cross-platform challenges\u2014myelosuppression, infectious risk, resistance monitoring and trial design\u2014and a pragmatic framework for moving beyond incrementalism toward durable control and cure.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2025.1696229","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T06:36:40Z","timestamp":1763534200000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Acute myeloid leukemia drug resistance: targetable nodes and the clinical trajectory of small-molecule inhibitors"],"prefix":"10.3389","volume":"16","author":[{"given":"Xixi","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yina","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shichao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijiu","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengtong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"6020","DOI":"10.3390\/ijms25116020","article-title":"Distinct responses to menin inhibition and synergy with DOT1L inhibition in KMT2A-rearranged acute lymphoblastic and myeloid leukemia","volume":"25","author":"Adriaanse","year":"2024","journal-title":"Int. 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