Issues

An inducible CDK6–INK4 complex blocks drug binding and impairs efficacy for current-generation CDK4/6 inhibitors, but harbors sensitivity to potent CDK4/6 degrader compounds that represent a promising strategy for next-generation cell-cycle inhibitors.

Analysis of data from the Extended Analysis for Leukemia/Lymphoma Treatment (EXALT) trial revealed that guidance of treatment decisions based on single-cell functional drug testing is achievable and efficacious in relapsed and refractory hematologic cancers.

Integration of ex vivo drug sensitivity testing with genomic and transcriptomic profiling via a functional and molecular tumor board in AML uncovered new opportunities for individualized patient therapy, functional taxonomy, and discovery of biomarkers.

In a large phase I trial, the irreversible FGFR1–4 inhibitor futibatinib demonstrated manageable safety and antitumor activity in a broad spectrum of FGFR-aberrant tumors, including FGFR2 fusion/rearrangement–positive cholangiocarcinoma.

Combined vandetanib and everolimus was identified by artificial intelligence as a potential therapy for ACVR1-mutant DIPG, as they synergize in vitro and extend survival in vivo, with preliminary testing in four children suggesting this combination as a feasible clinical option.

In vivo CRISPR screening in human AML models identified targets with high translational potential, including the myo-inositol transporter SLC5A3, which supports growth, and the E3 ligase MARCH5, which is crucial for maintenance of AML survival through apoptosis prevention.

CRISPR screens led to the identification of the inositol transporter SLC5A3 as an AML-specific dependency that stems from the loss of inositol biosynthesis capacity through an epigenetic mechanism.

Tracking and ablation of a specific CAF population reveals that a numerically minor CAF subtype from a defined cell of origin plays unique roles in establishing the pancreatic tumor microenvironment.

BPDCN, a male-biased leukemia, was found to harbor frequent male-restricted ZRSR2 mutations, with loss of this X chromosome gene causing poor dendritic cell response to inflammatory stimuli and impaired subsequent cell death.

MYC hyperactivation through genome amplification or transcriptional induction promotes a proinvasive tumor microenvironment and a more highly metastatic state in pancreas cancer.