Sequential drug treatment targeting cell cycle and cell fate regulatory programs blocks non-genetic cancer evolution in acute lymphoblastic leukemia

• Published in: Genome Biology Vol. 25; no. 1; pp. 143 - 38
• Main Authors: Malyukova, Alena, Lahnalampi, Mari, Falqués-Costa, Ton, Pölönen, Petri, Sipola, Mikko, Mehtonen, Juha, Teppo, Susanna, Akopyan, Karen, Viiliainen, Johanna, Lohi, Olli, Hagström-Andersson, Anna K, Heinäniemi, Merja, Sangfelt, Olle
• Format: Journal Article
• Language: English
• Published: England BioMed Central 31.05.2024; BMC
• Subjects: Acute lymphoblastic leukemia; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; AZD1775; B-ALL; Basic Medicine; BCL6; Cancer; Cancer therapies; Cell activation; Cell and Molecular Biology; Cell cycle; Cell Cycle - drug effects; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell death; Cell division; Cell fate; Cell Line, Tumor; Cell proliferation; Cell state transition; Cell- och molekylärbiologi; Chemotherapy; Chromatin state; Core Binding Factor Alpha 2 Subunit - genetics; Cyclin-dependent kinases; Diversification; DNA damage; DNA methylation; Drug dosages; Drug resistance; Drug tolerance; Gene loci; Genomes; Genomics; Histone-Lysine N-Methyltransferase - genetics; Humans; Immunological tolerance; Kinases; KMT2A-r; Leukemia; Lipid metabolism; Lymphatic leukemia; Lymphocytes B; Medical and Health Sciences; Medical prognosis; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mutation; Myc protein; Myeloid-Lymphoid Leukemia Protein - genetics; p53 Protein; Phosphorylation; Pre-BCR; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Protein-Tyrosine Kinases - antagonists & inhibitors; Proteins; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Pyrimidinones - pharmacology; Pyrimidinones - therapeutic use; RUNX1; Runx1 protein; Senescence; Single-cell multiomics; Toxicity; Transcription activation; Transcription factors; WEE1; AZD1775; B-ALL; WEE1; BCL6; Leukemia; Pre-BCR; KMT2A-r; Single-cell multiomics; Cell state transition; Chromatin state; RUNX1
• ISSN: 1474-760X; 1474-7596; 1474-760X
• DOI: 10.1186/s13059-024-03260-4

Targeted therapies exploiting vulnerabilities of cancer cells hold promise for improving patient outcome and reducing side-effects of chemotherapy. However, efficacy of precision therapies is limited in part because of tumor cell heterogeneity. A better mechanistic understanding of how drug effect is linked to cancer cell state diversity is crucial for identifying effective combination therapies that can prevent disease recurrence. Here, we characterize the effect of G2/M checkpoint inhibition in acute lymphoblastic leukemia (ALL) and demonstrate that WEE1 targeted therapy impinges on cell fate decision regulatory circuits. We find the highest inhibition of recovery of proliferation in ALL cells with KMT2A-rearrangements. Single-cell RNA-seq and ATAC-seq of RS4;11 cells harboring KMT2A::AFF1, treated with the WEE1 inhibitor AZD1775, reveal diversification of cell states, with a fraction of cells exhibiting strong activation of p53-driven processes linked to apoptosis and senescence, and disruption of a core KMT2A-RUNX1-MYC regulatory network. In this cell state diversification induced by WEE1 inhibition, a subpopulation transitions to a drug tolerant cell 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, ibrutinib, or perturbing metabolism by fatostatin or AZD2014 effectively counteracts drug tolerance by inducing cell death and repressing stemness markers. Collectively, our findings provide new insights into the tight connectivity of gene regulatory programs associated with cell cycle and cell fate regulation, and a rationale for sequential administration of WEE1 inhibitors with low toxicity inhibitors of pre-BCR signaling or metabolism.