Persistence of targetable lesions, predicted therapy sensitivity and proteomes through disease evolution in pediatric acute lymphoblastic leukemia

• DOI: 10.1101/2022.03.04.22271927
• Publication Date: 2022-03-09T03:10:11Z
• Authors: Amanda C. Lorentzian; Jenna Rever; Enes K. Ergin; Meiyun Guo; Neha M. Akella; Nina Rolf; C. James Lim; Gregor S.D. Reid; Christopher A. Ma...; Philipp F. Lange
• Keywords: Proteome; Persistence (discontinuity)

ABSTRACT Childhood acute lymphoblastic leukemia (ALL) genomes show that relapses often arise from subclonal outgrowths. However, the impact of clonal evolution on actionable proteome and response to targeted therapy is not known. Here, we present a comprehensive retrospective analysis paired ALL diagnosis relapsed specimen. Targeted next generation sequencing indicated persistence genome variants stable proteomes through disease progression. Paired viably-frozen biopsies showed high correlation drug variant-targeted therapies but in vitro selectivity was low. Proteome prioritized PARP1 as new pan-ALL target candidate needed for survival following cellular stress; diagnostic samples demonstrated robust sensitivity treatment with two PARP1/2 inhibitors. Together, these findings support initiating prospective precision oncology approaches at emphasize need incorporate prospectively determine tumor sensitivities, which are likely be retained relapse. STATEMENT OF SIGNIFICANCE We discover progression pediatric defined by targetable genomic proteomes, reveal candidates. Thus, personalized options childhood may improved incorporation proteogenomic initiated diagnosis.