Targetable lesions and proteomes predict therapy sensitivity through disease evolution in pediatric acute lymphoblastic leukemia.

Autor: Lorentzian AC; Department of Pediatrics, University of British Columbia, Vancouver, Canada.; Michael Cuccione Childhood Cancer Research Program at the BC Children's Hospital Research Institute, Vancouver, Canada., Rever J; Department of Pediatrics, University of British Columbia, Vancouver, Canada.; Michael Cuccione Childhood Cancer Research Program at the BC Children's Hospital Research Institute, Vancouver, Canada., Ergin EK; Michael Cuccione Childhood Cancer Research Program at the BC Children's Hospital Research Institute, Vancouver, Canada.; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada., Guo M; Department of Pediatrics, University of British Columbia, Vancouver, Canada.; Michael Cuccione Childhood Cancer Research Program at the BC Children's Hospital Research Institute, Vancouver, Canada., Akella NM; Department of Pediatrics, University of British Columbia, Vancouver, Canada.; Michael Cuccione Childhood Cancer Research Program at the BC Children's Hospital Research Institute, Vancouver, Canada., Rolf N; Department of Pediatrics, University of British Columbia, Vancouver, Canada.; Michael Cuccione Childhood Cancer Research Program at the BC Children's Hospital Research Institute, Vancouver, Canada., James Lim C; Department of Pediatrics, University of British Columbia, Vancouver, Canada.; Michael Cuccione Childhood Cancer Research Program at the BC Children's Hospital Research Institute, Vancouver, Canada., Reid GSD; Department of Pediatrics, University of British Columbia, Vancouver, Canada.; Michael Cuccione Childhood Cancer Research Program at the BC Children's Hospital Research Institute, Vancouver, Canada., Maxwell CA; Department of Pediatrics, University of British Columbia, Vancouver, Canada. cmaxwell@bcchr.ca.; Michael Cuccione Childhood Cancer Research Program at the BC Children's Hospital Research Institute, Vancouver, Canada. cmaxwell@bcchr.ca., Lange PF; Michael Cuccione Childhood Cancer Research Program at the BC Children's Hospital Research Institute, Vancouver, Canada. philipp.lange@ubc.ca.; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada. philipp.lange@ubc.ca.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Nov 21; Vol. 14 (1), pp. 7161. Date of Electronic Publication: 2023 Nov 21.
DOI: 10.1038/s41467-023-42701-9
Abstrakt: Childhood acute lymphoblastic leukemia (ALL) genomes show that relapses often arise from subclonal outgrowths. However, the impact of clonal evolution on the actionable proteome and response to targeted therapy is not known. Here, we present a comprehensive retrospective analysis of paired ALL diagnosis and relapsed specimen. Targeted next generation sequencing and proteome analysis indicate persistence of actionable genome variants and stable proteomes through disease progression. Paired viably-frozen biopsies show high correlation of drug response to variant-targeted therapies but in vitro selectivity is low. Proteome analysis prioritizes PARP1 as a pan-ALL target candidate needed for survival following cellular stress; diagnostic and relapsed ALL samples demonstrate robust sensitivity to treatment with two PARP1/2 inhibitors. Together, these findings support initiating prospective precision oncology approaches at ALL diagnosis and emphasize the need to incorporate proteome analysis to prospectively determine tumor sensitivities, which are likely to be retained at disease relapse.
(© 2023. The Author(s).)
Databáze: MEDLINE
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