Despite the clinical impact of venetoclax in acute myeloid leukemia (AML), acquired resistance remains a major barrier to durable response.
However, a new study, CHRNB4-Mediated Neuroactive Signaling Rewiring Drives Adaptive Resistance to BCL-2 Inhibition in Acute Myeloid Leukemia, published in Cancers by Case CCC Molecular Oncology Program member Shujun Liu, PhD, and Immune Oncology Program member William Tse, MD, MBA, defines a previously unrecognized mechanism underlying this resistance—and identifies a clinically actionable target.
Using transcriptomic profiling and integrated in vitro and in vivo models, the team showed that venetoclax-resistant AML cells transition to a hyperproliferative, aggressive state independent of canonical BCL-2–mediated apoptosis.
Resistant cells maintained growth despite suppression of BCL-2, MCL-1, and downstream apoptotic markers, indicating a functional bypass of the drug’s intended mechanism.
Pathway-level analysis identified the neuroactive ligand–receptor interaction (NLRI) pathway as a shared signaling node across resistant models.
Within this pathway, CHRNB4 was consistently downregulated in resistant cell lines and tumor models.
Functional studies demonstrated that restoring CHRNB4 expression significantly impaired colony formation and reduced tumor growth in vivo, establishing a direct role in mediating the resistant phenotype. In other words, according to the investigators, the research highlights a survival strategy where leukemia cells rewire themselves to ignore the drugs meant to kill them.
Clinical correlation further strengthens the translational relevance: low CHRNB4 expression is associated with shorter overall survival and diminished response to venetoclax, supporting its utility as a prognostic biomarker and potential stratification tool. Liu, Tse, and colleagues note that measuring CHRNB4 expression can potentially identify patients at higher risk for relapse, which could allow clinicians to adjust treatment earlier.
The team's work moves beyond descriptive resistance models to define a targetable mechanism and support development of multi-pathway therapeutic strategies that incorporate NLRI signaling modulation to prevent or overcome venetoclax resistance in AML.
Together, these results position CHRNB4 as both a biomarker of treatment response and a candidate therapeutic target in refractory AML.