Simultaneous Targeting of XPO1 and BCL2 as an Effective Treatment Strategy for Double-Hit Lymphoma

Abstract

Double-hit lymphoma (DHL) is among the most aggressive and chemoresistant lymphoma subtypes.DHLs carry genomic abnormalities in MYC, BCL2 and/or BCL6 oncogenes. Due to simultaneous overexpression of these driver oncogenes, DHLs are highly resistant to the frontline therapies. Most DHLs overexpress both MYC and BCL2 driver oncogenes concurrently. We reasoned that simultaneous suppression of the two driver oncogenes would be more effective in eradicating DHLs than inactivation of single oncogene. XPO1 is a receptor for nuclear cytoplasmic transport of protein and RNA species. Recently, XPO1 inhibition was shown to downregulate MYC expression in several cancer cell lines. We therefore examined the role of XPO1 as a therapeutic target in suppressing MYC function and the potential synergistic effects of simultaneous suppression of XPO1 and BCL2 in the treatment of DHL. Here, we demonstrate that XPO1 inhibition abrogates MYC protein expression and induces massive tumor cell apoptosis. Combined use of XPO1 and BCL2 inhibitors is highly effective in eradicating DHL cells in cell culture. Notably, in a mouse model of DHL bearing primary tumor cells derived from lymphoma patients, combined treatment with XPO1 and BCL2 inhibitors blocks tumor progression, prevents brain metastasis, and extends host survival. Thus, our study confirms the simultaneous targeting of MYC and BCL2 driver oncogenes through the combined use of XPO1 and BCL2 inhibitors as a unique approach for the treatment of DHLs. Key WordsDouble-hit lymphoma, MYC, BCL2, XPO1, targeted therapy, combination therapy. Introduction:Double-hit lymphoma (DHL) is a subtype of Non-Hodgkin's Lymphoma (NHL) with genomic abnormalities in MYC and BCL2 (and less frequently BCL6), leading to the overexpression of these driver oncogenes. The prognosis for the majority of NHLs has improved significantly in the past decades due to the development of chemotherapy, targeted therapy, and immunotherapy. In comparison, DHL remains highly resistant and refractory to the first line immunochemotherapy, R-CHOP, with a 5year overall survival rate of 30% [1,2].The co-existence of multiple oncogenic events in DHLs, including MYC, BCL2, and BCL6, provides an opportunity for combined targeted therapy. As the two common drivers of DHL, MYC and BCL2 cooperate in lymphomagenesis and tumor maintenance. A combined therapy aimed at targeting both MYC and BCL2 may arguably be more effective than suppressing either MYC or BCL2 alone in eradicating the tumors cells [3,4]. Among several BCL2 inhibitors, ABT-199, was developed and tested in clinical trials, and approved by FDA for the treatment of chronic lymphocytic leukemia [5]. In contrast, direct targeting of MYC has proven challenging due to its structural property as a transcription factor.XPO1 is an adaptor of nuclear export for many protein and RNA species. Recent studies suggest that XPO1 may regulate nuclear export of mRNAs encoding several oncoproteins, such as MYC, BCL2, Cyclin D1, and PIM1 [6][7][8]. Moreover, suppression of XPO1 with selecti...

Rational Targeted Therapeutics for Double-Hit Lymphoma

“…Combined use of XPO1 and BCL2 inhibitors is highly synergistic in vitro in eradicating DHL cells. In a mouse model of DHL bearing primary patient-derived xenograft tumor cells, combined treatment with XPO1 and BCL2 inhibitors blocks tumor progression and extends host survival [9]. Of particular interest, we found that the animals treated with the drug combination exhibit significantly lower brain metastasis compared with other groups.…”

Prevalence, distribution and predictive value of XPO1 mutation in a real‐life chronic lymphocytic leukaemia cohort

“…Nonetheless, recent experimental studies suggest that XPO1 ‐mutated cells are preferentially sensitive to XPO1 inhibitors 7 . Moreover, the combination of XPO1 and BCL2 inhibitors blocks tumour progression and extends survival in a lymphoma mouse model 15 . These experimental data suggest that combining XPO1 inhibitors with BH3‐mimetic‐based therapy could be of interest in R/R patients with XPO1 mutations.…”