Synthetic lethal targeting of EBV-positive diffuse large B cell lymphomas in persons living with HIV

PROJECT SUMMARY
Diffuse large B-cell lymphoma (DLBCL), the commonest type of non-Hodgkin lymphoma (NHL), is highly
aggressive and despite antiretrovirals continues to be a leading cause of cancer-related death in persons living
with HIV. Notably, up to 90% of HIV-DLBCL are positive for the cancer-causing Epstein-Barr virus (EBV). Thus,
understanding how EBV contributes to cancer is essential to discovering new therapeutic approaches.
Cancer cells require DNA repair but how EBV engages and reshapes cellular DNA repair is an underexplored
area. Our studies on EBV-cancer cells and EBV-transformed human B cells (lymphoblastoid cell lines), the latter
an important model of EBV-driven lymphomas in immunosuppressed hosts, converge on STAT3. An
oncoprotein, STAT3 is frequently activated in cancer. Several studies have also shown that EBV+ HIV-DLBCL
frequently exhibit activating mutations in the Janus kinase (JAK)-STAT3 pathway. We have found that EBV
activates STAT3 to circumvent the S phase checkpoint barrier, thereby ensuring cell proliferation but in the
process, loses homologous recombination (HR) that repairs DNA double strand breaks (DSB). As a result, EBV-
transformed and cancer cells become dependent on other forms of DNA repair, in particular, the error-prone
microhomology-mediated end-joining (MMEJ) type of repair. This creates a therapeutic vulnerability to synthetic
lethal agents that would otherwise be non-toxic to cells with intact HR. PARP [poly (ADP-ribose) polymerase]
inhibitors are among such synthetic lethal agents that target MMEJ. Indeed, we find that EBV-transformed and
cancer cells are highly susceptible to MMEJ inhibitors that target PARP and the MMEJ-specific DNA polymerase,
POLθ. Supporting this dependence on MMEJ, EBV-transformed cells exhibit genome-wide scars of MMEJ
repair, and, EBV+ HIV-DLBCL display higher abundance of STAT3 and POLQ transcripts compared to EBV-
tumors; POLQ encodes POLθ. Further, by multiomic analyses of several hundred cancer cell lines, we have
identified a STAT3-related gene expression signature that points to a mechanistic link between STAT3 and
reliance on MMEJ repair while predicting susceptibility to synthetic lethal therapies.
We now propose to investigate how EBV uses the JAK-STAT3 pathway to reshape DNA repair and render EBV+
HIV-DLBCL vulnerable to synthetic lethal therapeutic targeting. Using cell lines, xenografts, and patient-derived
EBV+ & EBV- HIV-DLBCL from the NCI AIDS and Cancer Specimen Resource (ACSR), we investigate the link
between JAK-STAT3 pathway and DSB repair in EBV+ HIV-DLBCL (Aim 1) and synthetic-lethally exploit JAK-
STAT3-dependent DNA repair deficiency to kill EBV+ HIV-DLBCL (Aim 2).
These studies specifically address PAR-21-348 by identifying mechanisms and generating new paradigms to
reveal how EBV contributes to NHL. In the long-term, these mechanistic insights will uncover novel vulnerabilities
and enable the prediction of responses to synthetic lethal therapies to improve outcomes for EBV+ DLBCL in
persons living with HIV.

Grant Number: 5U01CA275310-04
NIH Institute/Center: NIH
Principal Investigator: SUMITA BHADURI-MCINTOSH