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

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 indicated persistence of actionable genome variants and stable proteomes through disease progression. Paired viably-frozen biopsies showed high correlation of drug response to variant-targeted therapies but in vitro selectivity was low. Proteome analysis prioritized PARP1 as a new pan-ALL target candidate needed for survival following cellular stress; diagnostic and relapsed ALL samples demonstrated 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. STATEMENT OF SIGNIFICANCE We discover that disease progression and evolution in pediatric acute lymphoblastic leukemia is defined by the persistence of targetable genomic variants and stable proteomes, which reveal pan-ALL target candidates. Thus, personalized treatment options in childhood ALL may be improved with the incorporation of prospective proteogenomic approaches initiated at disease diagnosis. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Michael Cuccione Foundation (MCF) and the BC Childrens Hospital Foundation through the Better Responses through Avatars and Evidence (BRAVE) Initiative. Salary support was provided by the MCF (CJL, GSDR, CAM, PFL), the Canada Research Chairs Program (PFL), the Michael Smith Foundation for Health Research Scholar Program (PFL) and the University of British Columbia (AL, EKE). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Sample collection and experiments were performed as approved by the University of British Columbia BC Childrens and Womens Research Ethics Board I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors