Proteomic and phosphoproteomic measurements enhance ability to predict ex vivo drug response in AML

Abstract

Acute Myeloid Leukemia (AML) affects 20,000 patients in the US annually with a five-year survival rate of approximately 25%. One reason for the low survival rate is the high prevalence of clonal evolution that gives rise to heterogeneous sub-populations of leukemic cells with diverse mutation spectra, which eventually leads to disease relapse. This genetic heterogeneity drives the activation of complex signaling pathways that is reflected at the protein level. This diversity makes it difficult to treat AML with targeted therapy, requiring custom patient treatment protocols tailored to each individual’s leukemia. Toward this end, the Beat AML research program prospectively collected genomic and transcriptomic data from over 1000 AML patients and carried out ex vivo drug sensitivity assays to identify genomic signatures that could predict patient-specific drug responses. However, there are inherent weaknesses in using only genetic and transcriptomic measurements as surrogates of drug response, particularly the absence of direct information about phosphorylation-mediated signal transduction. As a member of the Clinical Proteomic Tumor Analysis Consortium, we have extended the molecular characterization of this cohort by collecting proteomic and phosphoproteomic measurements from a subset of these patient samples (38 in total) to evaluate the hypothesis that proteomic signatures can improve the ability to predict response to 26 drugs in AML ex vivo samples. In this work we describe our systematic, multi-omic approach to evaluate proteomic signatures of drug response and compare protein levels to other markers of drug response such as mutational patterns. We explore the nuances of this approach using two drugs that target key pathways activated in AML: quizartinib (FLT3) and trametinib (Ras/MEK), and show how patient-derived signatures can be interpreted biologically and validated in cell lines. In conclusion, this pilot study demonstrates strong promise for proteomics-based patient stratification to assess drug sensitivity in AML.

Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children

“…A few studies have performed global proteomics and phosphoproteomics on AML patient material (e.g., [9][10][11][12][13][14][15][16][17]). The studies carried out thus far mainly served to identify diagnostic or prognostic markers, or to investigate the efficacy of novel treatments.…”

Mass Spectrometry–Based Proteogenomics: New Therapeutic Opportunities for Precision Medicine

“…MS-based proteomic approaches mapped the effects of targeted agents on AML cell lines and primary samples and identified key pathways affected by drug treatment ( 33 – 35 ) and mutational status ( 36 ) or targetable pathways associated with drug resistance ( 37 , 38 ). We previously used computational approaches to integrate proteomic profiling with genomics, transcriptomics, and small-molecule inhibitor sensitivity data sets to create models that recapitulate patient biology, which can be leveraged to prioritize treatment strategies ( 37 , 39 ).…”

Proteomic Characterization of Acute Myeloid Leukemia for Precision Medicine

“…In another study that used ML from mass spectrometry data to derive models of therapeutic response and mechanistic inference in AML cases, Gosline et al. ( 101 ) performed proteomics and phosphoproteomics from 38 AML cases for which genomics and transcriptomics data were available. Identified signatures from different omic layers were evaluated for their ability to model ex vivo responses to 26 drugs.…”