Putting the STING back into BH3-mimetic drugs for TP53-mutant blood cancers

Diepstraten, ST; Yuan, Y; La Marca, JE; Young, S; Chang, C; Whelan, L; Ross, AM; Fischer, KC; Pomilio, G; Morris, R; Georgiou, A; Litalien, V; Brown, FC; Roberts, AW; Strasser, A; Wei, AH; Kelly, GL

Author(s): Diepstraten, ST; Yuan, Y; La Marca, JE; Young, S; Chang, C; Whelan, L; Ross, AM; Fischer, KC; Pomilio, G; Morris, R; Georgiou, A; Litalien, V; Brown, FC; Roberts, AW; Strasser, A; Wei, AH; Kelly, GL;
Details: Publication Year 2024-05-13,Volume 42,Issue #5,Page 850-868
Journal Title: Cancer Cell
Publication Type: Research article
Abstract: TP53-mutant blood cancers remain a clinical challenge. BH3-mimetic drugs inhibit BCL-2 pro-survival proteins, inducing cancer cell apoptosis. Despite acting downstream of p53, functional p53 is required for maximal cancer cell killing by BH3-mimetics through an unknown mechanism. Here, we report p53 is activated following BH3-mimetic induced mitochondrial outer membrane permeabilization, leading to BH3-only protein induction and thereby potentiating the pro-apoptotic signal. TP53-deficient lymphomas lack this feedforward loop, providing opportunities for survival and disease relapse after BH3-mimetic treatment. The therapeutic barrier imposed by defects in TP53 can be overcome by direct activation of the cGAS/STING pathway, which promotes apoptosis of blood cancer cells through p53-independent BH3-only protein upregulation. Combining clinically relevant STING agonists with BH3-mimetic drugs efficiently kills TRP53/TP53-mutant mouse B lymphoma, human NK/T lymphoma, and acute myeloid leukemia cells. This represents a promising therapy regime that can be fast-tracked to tackle TP53-mutant blood cancers in the clinic.
Publisher: Cell Press
Keywords: *Tumor Suppressor Protein p53/genetics; Humans; Animals; Mice; *Membrane Proteins/genetics; *Apoptosis/drug effects; Cell Line, Tumor; Mutation; Hematologic Neoplasms/drug therapy/genetics; Proto-Oncogene Proteins c-bcl-2/genetics; Peptide Fragments/pharmacology; Antineoplastic Agents/pharmacology/therapeutic use; Signal Transduction/drug effects; Proto-Oncogene Proteins/genetics; BH3-mimetic drugs; Sting; acute myeloid leukemia; apoptosis; blood cancer; lymphoma; p53
Department(s): Clinical Haematology
Publisher's Version: https://doi.org/10.1016/j.ccell.2024.04.004
Open Access at Publisher's Site: https://doi.org/10.1016/j.ccell.2024.04.004
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-07-04 04:37:43

Last Modified: 2024-07-04 04:49:35