Pre-Clinical Assessment of MCL-1 as a Therapeutic Target in T-Cell Lymphomas

Abstract

Patients with T-cell non-Hodgkin lymphoma (T-NHL) face a particularly poor prognosis and are in desperate need of improved targeted therapies and rational combination strategies, especially in the relapsed/refractory setting. Evasion of apoptosis is a hallmark of cancer cells and contributes to drug resistance and tumor progression (Hanahan & Weinberg, 2000). Thus, activation of intrinsic apoptosis is a promising avenue for treatment of a variety of cancers, and drugs targeting specific parts of the pathway are already in clinical use (Ashkenazi et al., 2017). A common mechanism by which lymphomas evade apoptosis is upregulation of anti-apoptotic BCL-2 family members. MCL-1 is the most universally expressed of the BCL-2 family members across a panel of different T-NHL subtypes (Spinner et al., 2016), making it an attractive target in T-NHL. Here we characterize the BCL-2 family members by protein abundance, RNA expression, and copy number variations across a set of 21 T-NHL cell lines and 5 patient-derived xenograft models. To functionally assess the intrinsic apoptosis pathway, we utilized a functional assay called BH3 profiling. BH3 profiling identified MCL-1 dependence across multiple subtypes of T-cell lymphomas. Subsequently we tested the in vitro activity of an MCL-1 inhibitor, AZD5991, using a luminescent cell viability assay. As predicted by BH3-profiling, 15 of 21 tested cell lines showed sensitivity to AZD5991. In contrast, there was little correlation between drug sensitivity and either MCL-1 protein abundance or RNA expression. The in vivo efficacy of MCL-1 inhibition in PDX models of T-NHL correlated with functional dependence on MCL-1, as measured by BH3 profiling. These data provide support for a biomarker-driven therapeutic approach to select T cell lymphomas that are dependent on MCL-1.