Page 10 - Haematologica - Vol. 105 n. 6 - June 2020

Editorials
Keys to drug sensitivity from updated functional work flows
Stephen E. Kurtz1 and Jeffrey W. Tyner1,2
1Division of Hematology and Medical Oncology and 2Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
E-mail: JEFFREY W. TYNER - tynerj@ohsu.edu doi:10.3324/haematol.2020.250662
Aprimary goal of cancer therapy is to match patients with the most appropriate drug regimens. Identifying characteristics of patients who respond to therapies and devising alternative strategies for non-responsive patients are important clinical consid- erations. Next generation sequencing (NGS) has provided a central technology to reveal genetic alterations and guide this process. Additionally, the development of can- cer therapies that target specific signaling pathways and subcellular components has increased the opportunity for matching patients with molecularly targeted drugs. In practice, however, limitations in understanding the rela- tionship between cancer genotypes and their correspon- ding phenotypes have hindered this process; somatic can- cer mutations do not always reliably suggest therapies. Indeed, in some cases, targeted drugs have shown clinical utility when matched to cell phenotypes rather than somatic genotype. In this way, the use of orthogonal technologies, such as functional testing and immune-pro- filing, integrated with NGS holds promise to improve outcomes by better matching therapies to individual patients.1 In addition, lack of durable efficacy of many categories of therapies has sometimes been attributed to inadequate elimination or targeting of leukemic stem/progenitor cells (reviewed by Rossi et al.2).
In this issue, Majumder et al. report on the manner by which understanding of innate drug sensitivities in healthy hematopoietic cells advances both the identifica- tion of lineage-specific anti-cancer therapies as well as off- target drug effects in treating acute myeloid leukemia.3 Underlying this work is the well-characterized biology of hematopoiesis whereby multipotent stem cells and pre- cursors differentiate through distinct signaling pathways to generate a set of blood cell types with discrete pheno- types and functions. The authors surmise that malignant hematopoietic cells use the same signaling pathways; con- sequently, they leverage specific pathways from normal cells as a means to identify cancer therapies for their malignant counterparts. Conversely, the authors note that drug responses seen in healthy cells may reveal potential adverse effects.
The authors augment their established cell-based screening platform for identifying anti-leukemia drugs4 with high capacity flow cytometry (Figure 1A). This tech- nological development permits the simultaneous evalua- tion of drug responses from multiple hematopoietic cell populations based on their respective surface antigens. Drug responses are mapped to proteome and cell type specific signaling profiles using mass spectrometry and mass cytometry. In this study, sensitivities to 71 small molecules were simultaneously assessed using multi-para- metric flow cytometry and then mapped to proteomic and signaling profiles to characterize the spectrum of drug
responses in various hematopoietic cell types. Across healthy cell types for B cells, natural killer (NK) cells, helper T cells, cytotoxic T cells and monocytes, the authors identify cell lineage-specific drug responses to define a global view of response profiles. By comparing drug responses between healthy and neoplastic cells, they show that healthy cell responses predict drug responses in corresponding malignant cells. The authors evaluate this screening approach on a large cohort of primary samples obtained from healthy donors and patients with myeloid and lymphoid leukemias, providing evidence that this method identifies new applications for the tested drugs.
A key highlight of this study is the profile observed for the BCL2 inhibitor, venetoclax, which revealed dose- dependent sensitivities across the hematopoietic cell types (Figure 1B). At the ends of this spectrum, B cells (CD19+) were the most sensitive whereas monocytes and granulo- cytes were the least sensitive to venetoclax. Moderate sensitivities were observed on cytotoxic and helper T cells (CD3+CD4- and CD3+CD4+), NK cells (CD56+), and NK-T cells (CD3+CD56+). Venetoclax had similar cell-specific effects regardless of disease status (healthy vs. malignant) indicating the variable nature of response to venetoclax is lineage specific. In addition, the study found an inverse relationship between venetoclax sensitivity and levels of phosphorylated STAT3. Monocytes and granulocytes have the highest levels of phosphorylated STAT3 and the lowest venetoclax sensitivity, perhaps reflecting the differ- ent transcriptional programs defining these two cell types.
Previous work by these authors and others indicated that BCL2 is differentially expressed in subpopulations of AML cells enriched for malignant stem/progenitor cells compared to more differentiated tumor cells5 and that venetoclax sensitivity in primary AML cells with a mono- cytic phenotype is reduced.6 These observations led to the hypothesis that clinical features of AML indicative of myeloid differentiation status may correlate with reduced BCL2 dependence in AML patients. Indeed, the veneto- clax response profile in this study is consistent with recent findings correlating venetoclax sensitivity with stages of AML disease differentiation as defined by flow cytometry.7 In the context of venetoclax-based therapies, phenotypically primitive AML is sensitive whereas mono- cytic AML is more resistant, due to intrinsic properties of monocytic AML cells including loss of BCL2 expression and reliance on MCL1 to mediate oxidative phosphoryla- tion and survival.
Cumulatively, these findings raise the possibility of new definitions for stem/progenitor cells in hematologic malig- nancies; definitions that would be based on propensity of cell types of any maturation state to persist in the face of a selective pressure. In some ways, these findings may also call into question the long-held notions that targeting
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