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

Amanda C. Lorentzian, Jenna Rever, Enes K. Ergin, Meiyun Guo, Neha M. Akella, Nina Rolf, C. James Lim, Gregor S. D. Reid, Christopher A. Maxwell () and Philipp F. Lange ()
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Amanda C. Lorentzian: University of British Columbia
Jenna Rever: University of British Columbia
Enes K. Ergin: Michael Cuccione Childhood Cancer Research Program at the BC Children’s Hospital Research Institute
Meiyun Guo: University of British Columbia
Neha M. Akella: University of British Columbia
Nina Rolf: University of British Columbia
C. James Lim: University of British Columbia
Gregor S. D. Reid: University of British Columbia
Christopher A. Maxwell: University of British Columbia
Philipp F. Lange: Michael Cuccione Childhood Cancer Research Program at the BC Children’s Hospital Research Institute

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-42701-9

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