Targeting mitochondrial respiration and the BCL2 family in high‐grade MYC‐associated B‐cell lymphoma

Abstract

Multiple molecular features, such as activation of specific oncogenes (e.g., MYC, BCL2) or a variety of gene expression signatures, have been associated with disease course in diffuse large B‐cell lymphoma (DLBCL), although their relationships and implications for targeted therapy remain to be fully unraveled. We report that MYC activity is closely correlated with—and most likely a driver of—gene signatures related to oxidative phosphorylation (OxPhos) in DLBCL, pointing to OxPhos enzymes, in particular mitochondrial electron transport chain (ETC) complexes, as possible therapeutic targets in high‐grade MYC‐associated lymphomas. In our experiments, indeed, MYC sensitized B cells to the ETC complex I inhibitor IACS‐010759. Mechanistically, IACS‐010759 triggered the integrated stress response (ISR) pathway, driven by the transcription factors ATF4 and CHOP, which engaged the intrinsic apoptosis pathway and lowered the apoptotic threshold in MYC‐overexpressing cells. In line with these findings, the BCL2‐inhibitory compound venetoclax synergized with IACS‐010759 against double‐hit lymphoma (DHL), a high‐grade malignancy with concurrent activation of MYC and BCL2. In BCL2‐negative lymphoma cells, instead, killing by IACS‐010759 was potentiated by the Mcl‐1 inhibitor S63845. Thus, combining an OxPhos inhibitor with select BH3‐mimetic drugs provides a novel therapeutic principle against aggressive, MYC‐associated DLBCL variants.

Activation of the Integrated Stress Response overcomes multidrug resistance in FBXW7-deficient cells

“…Second, increased levels of MYC have been shown to increase resistance to several therapies 24,68 . Finally, MYC overexpression renders cancer cells sensitive to targeting mitochondrial activity with antibiotics 69 or drugs targeting OXPHOS 70 . Given the increasing availability of chemical- or peptide-based therapies for targeting MYC 71 , whether these agents might be useful as a general strategy to overcome the MDR in cancer emerges as an interesting possibility.…”

Oxidative stress potentiates the therapeutic action of a mitochondrial complex I inhibitor in MYC-driven B-cell lymphoma

“…Since the ISR can also be activated by oxidative stress 29,30 , we tested whether NAC could counteract the action of IACS-010759 in triggering this response, as assayed by accumulation of the ISR-associated transcription factors ATF4 and CHOP. Indeed, while both proteins readily accumulated in OHT/IACS-010759 treated cells 16 , this effect was largely abrogated in the presence of NAC (Figure 2F). Finally, antibiotics that inhibit the mitochondrial ribosome and consequently suppress OxPhos activity (e. g. tigecycline and other tetracyclines) also activate the ISR [31][32][33][34] .…”

“…To further monitor the oxidative stress induced by OHT and IACS-010759 in FL MycER cells, we quantified the ratio of reduced to oxidized glutathione (GSH and GSSG, respectively) after 40 hours of IACS-010759 treatment, a time preceding overt cell death (observed at ca. 48h) 16 . Remarkably, each agent alone caused a moderate decrease in GSH/GSSG ratio, which became more pronounced in double treated cells (Figure 2A).…”

“…IACS-010759 was suspended in 0.5% methylcellulose (Merck Life Science), while ascorbate was dissolved in physiological saline. 16 , with the following qvalues: * q ≤ 0.05; ** q ≤ 0.01; **** q ≤ 0.0001.…”

“…We previously showed that ectopic activation of the 4-Hydroxytamoxifen (OHT)-responsive MycER TM chimaera (MycER) in the lymphoid precursor cell line FL5.12 (hereafter FL MycER cells) augmented OxPhos-associated gene expression and respiratory activity, and sensitized cells to apoptotic killing by the ETC complex I inhibitor IACS-010759 16 . To unravel possible MYC-effector pathways underlying this effect, we further queried our previous transcriptomic data 16 . This analysis pointed to the Nrf2-mediated oxidative stress response as the top activated pathway in OHTtreated FL MycER cells, regardless of IACS-010759 (Figure 1A).…”