Cottonham, C. | bioRxiv Science

bioRxiv2025

TP53 Inactivation Confers Resistance to the Menin Inhibitor Revumenib in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a heterogeneous cancer that is associated with poor outcomes. Revumenib and other menin inhibitors have shown promising activity against AMLs with KMT2A-rearrangements or NPM1 mutations. However, mechanisms of de novo resistance have not yet been elucidated. We analyzed a panel of cell lines and generated an isogenic model to assess the impact of TP53 mutations on the response of AML cells to revumenib. TP53 mutations are associated with de novo resistance to revumenib, impaired induction of TP53 transcriptional targets, and deregulated expression of the BH3 proteins BCL-2 and MCL-1. The MCL-1 inhibitor MIK665, but not venetoclax, preferentially sensitized TP53-mutant AML cells to revumenib. These data identify mutant TP53 as a potential biomarker for de novo resistance to revumenib, and provide a rationale to evaluate MCL-1 and menin inhibitor combinations in patients KMT2A-rearranged leukemias with TP53 mutations.

cancer biology↗

bioRxiv2024

Notch signaling maintains a progenitor-like subclass of hepatocellular carcinoma

Hepatocellular carcinomas (HCCs) constitute one of the few cancer indications for which mortality rates continue to rise. While Notch signaling dictates a key progenitor lineage choice during development, its role in HCC has remained controversial. Using therapeutic antibodies targeting Notch ligands and receptors to screen over 40 patient-derived xenograft models, we here identify progenitor-like HCCs that crucially depend on a tumor-intrinsic JAG1-NOTCH2 signal. Inhibiting this signal induces tumor regressions by triggering progenitor-to-hepatocyte differentiation, the same cell fate-switch that Notch controls during development. Transcriptomic analysis places the responsive tumors within the well-characterized progenitor subclass, a poor prognostic group of highly proliferative tumors, providing a diagnostic method to enrich for Notch-dependent HCCs. Furthermore, single-cell RNA sequencing uncovers a heterogeneous population of tumor cells and reveals how Notch inhibition shifts cells from a mixed cholangiocyte-hepatocyte lineage to one resembling mature hepatocytes. Analyzing the underlying transcriptional programs brings molecular detail to this process by showing that Notch inhibition de-represses expression of CEBPA, which enables the activity of HNF4, a hepatocyte lineage factor that is otherwise quiescent. We thus describe a compelling and targetable dependency in a poor-prognosis class of HCCs.

cancer biology↗