KEY TAKEAWAYS
- The study aimed to understand how drug effects relate to cancer cell diversity to find effective combination therapies.
- The results revealed insights into gene regulation and support sequential WEE1 and low-toxicity pre-BCR inhibitor therapy.
Targeted therapies that exploit cancer cell vulnerabilities show promise for improving patient outcomes and reducing chemotherapy side effects. However, the efficacy of precision therapies is partly limited by tumor cell heterogeneity. Understanding how drug effects are linked to the diversity of cancer cell states is crucial for identifying effective combination therapies to prevent disease recurrence.
Alena Malyukova and the team aimed to understand how G2/M checkpoint inhibition affects cell fate in acute lymphoblastic leukemia (ALL) to improve combination therapies.
Researchers characterized the effect of G2/M checkpoint inhibition in ALL, demonstrating that WEE1 targeted therapy affects cell fate decision regulatory circuits. They observed the highest inhibition of proliferation recovery in ALL cells with KMT2A rearrangements. Using single-cell RNA-seq and ATAC-seq on RS4, 11 cells harboring KMT2A::AFF1 were treated with the WEE1 inhibitor AZD1775, and they found a diversification of cell states.
A fraction of cells showed strong activation of p53-driven processes linked to apoptosis and senescence and disruption of a core KMT2A-RUNX1-MYC regulatory network. In this WEE1 inhibition-induced cell state diversification, some cells transitioned to a drug-tolerant state, characterized by activation of transcription factors regulating pre-B cell fate, lipid metabolism, and pre-BCR signaling in a reversible manner. Sequential treatment with BCR-signaling inhibitors dasatinib or ibrutinib, or metabolism perturbation by fatostatin or AZD2014, effectively countered drug tolerance by inducing cell death and repressing stemness markers.
The study concluded that gene regulatory programs associated with cell cycle and cell fate regulation are tightly connected. It provides a rationale for the sequential administration of WEE1 inhibitors with low-toxicity inhibitors of pre-BCR signaling or metabolism.
No funding information was available.
Source: https://pubmed.ncbi.nlm.nih.gov/38822412/
Malyukova A, Lahnalampi M, Falqués-Costa T, et al. (2024). “Sequential drug treatment targeting cell cycle and cell fate regulatory programs blocks non-genetic cancer evolution in acute lymphoblastic leukemia.” Genome Biol. 2024 May 31;25(1):143. doi: 10.1186/s13059-024-03260-4. PMID: 38822412; PMCID: PMC11143599.
