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

Area of Science:

• Oncology
• Genomics
• Proteomics

Background:

• Childhood acute lymphoblastic leukemia (ALL) relapses often originate from subclonal genetic expansions.
• The effect of clonal evolution on the actionable proteome and targeted therapy response in ALL is largely unknown.

Purpose of the Study:

• To investigate the impact of clonal evolution on the actionable proteome in paired diagnosis and relapsed childhood ALL specimens.
• To assess the correlation between genomic variants, proteome stability, and response to targeted therapies.

Main Methods:

• Retrospective analysis of paired ALL diagnosis and relapsed specimens.
• Targeted next-generation sequencing and proteome analysis.
• In vitro drug sensitivity assays using viably-frozen biopsies.

Main Results:

• Actionable genomic variants and proteomes remained largely stable from diagnosis to relapse.
• In vitro drug response correlated with variant-targeted therapies, but selectivity was low.
• Proteome analysis identified PARP1 as a pan-ALL target crucial for survival under cellular stress.

Conclusions:

• PARP1 is a promising therapeutic target in ALL, with both diagnostic and relapsed samples showing sensitivity to PARP1/2 inhibitors.
• Prospective precision oncology approaches incorporating proteome analysis at ALL diagnosis are warranted.
• Proteome profiling can predict tumor sensitivities likely to persist at relapse.