XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53

Manman Deng, Mingzhi Zhang, Zijun Y Xu-Monette, Lan V Pham, Alexandar Tzankov, Carlo Visco, Xiaosheng Fang, Govind Bhagat, Feng Zhu, Karen Dybkaer, April Chiu, Wayne Tam, Youli Zu, Eric D Hsi, William W L Choi, Jooryung Huh, Maurilio Ponzoni, Andrés J M Ferreri, Michael B Møller, Benjamin M Parsons, J Han van Krieken, Miguel A Piris, Jane N Winter, Fredrick Hagemeister, Lapo Alinari, Yong Li, Michael Andreeff, Bing Xu, Ken H Young, Manman Deng, Mingzhi Zhang, Zijun Y Xu-Monette, Lan V Pham, Alexandar Tzankov, Carlo Visco, Xiaosheng Fang, Govind Bhagat, Feng Zhu, Karen Dybkaer, April Chiu, Wayne Tam, Youli Zu, Eric D Hsi, William W L Choi, Jooryung Huh, Maurilio Ponzoni, Andrés J M Ferreri, Michael B Møller, Benjamin M Parsons, J Han van Krieken, Miguel A Piris, Jane N Winter, Fredrick Hagemeister, Lapo Alinari, Yong Li, Michael Andreeff, Bing Xu, Ken H Young

Abstract

The XPO1 inhibitor selinexor was recently approved in relapsed/refractory DLBCL patients but only demonstrated modest anti-DLBCL efficacy, prompting us to investigate the prognostic effect of XPO1 in DLBCL patients and the rational combination therapies in high-risk DLBCL. High XPO1 expression (XPO1high) showed significant adverse prognostic impact in 544 studied DLBCL patients, especially in those with BCL2 overexpression. Therapeutic study in 30 DLBCL cell lines with various molecular and genetic background found robust cytotoxicity of selinexor, especially in cells with BCL2-rearranged (BCL2-R+) DLBCL or high-grade B-cell lymphoma with MYC/BCL2 double-hit (HGBCL-DH). However, expression of mutant (Mut) p53 significantly reduced the cytotoxicity of selinexor in overall cell lines and the BCL2-R and HGBCL-DH subsets, consistent with the favorable impact of XPO1high observed in Mut-p53-expressing patients. The therapeutic effect of selinexor in HGBCL-DH cells was significantly enhanced when combined with a BET inhibitor INCB057643, overcoming the drug resistance in Mut-p53-expressing cells. Collectively, these data suggest that XPO1 worsens the survival of DLBCL patients with unfavorable prognostic factors such as BCL2 overexpression and double-hit, in line with the higher efficacy of selinexor demonstrated in BCL2-R+ DLBCL and HGBCL-DH cell lines. Expression of Mut-p53 confers resistance to selinexor treatment, which can be overcome by combined INCB057643 treatment in HGBCL-DH cells. This study provides insight into the XPO1 significance and selinexor efficacy in DLBCL, important for developing combination therapy for relapsed/refractory DLBCL and HGBCL-DH.

Keywords: BCL2; DLBCL; HGBCL; MYC; Selinexor; TP53 mutation; XPO1.

Conflict of interest statement

All authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
Impact of XPO1 expression on patient survival in DLBCL. a In the entire cohort, DLBCL patients with high level of XPO1 expression (XPO1high) had significantly worse OS and PFS than those with low or negative XPO1 expression (XPO1low). b XPO1high remarkably worsened the OS/PFS of DLBCL patients with BCL2high expression. c XPO1high significantly worsened the OS/PFS of patients with dual MYChighBCL2high expression, and showed a trend of unfavorable effect on OS in patients with dual MYC/BCL2 rearrangements (MYC-R+BCL2-R+, HGBCL-DH). d In TP53-mutated (Mut) DLBCL patients without Mut-p53 overexpression, XPO1high showed a trend of unfavorable prognostic effect on OS. e In Mut-TP53 DLBCL patients with Mut-p53 overexpression, XPO1high showed favorable prognostic effect, which was not significant in overall patients but significant in the subset with low BCL2 expression. f Significantly differentially expressed genes between XPO1high and XPO1low patients with concurrent Mut-TP53 and MYChigh
Fig. 2
Fig. 2
Therapeutic effect of selinexor alone or in combination with a BET inhibitor INCB057643 in DLBCL cellular models. a The effect of 72-h selinexor exposure on cell viability of 30 DLBCL cell lines. Waterfall graph showed the specific IC50 value of selinexor for each cell line with either ABC or GCB subtype of DLBCL. b DLBCL cell lines with BCL2 rearrangement (BCL2-R) or HGBCL-DH were more sensitive to selinexor with a lower mean IC50 value compared with other cell lines. c The presence of mutant (Mut) p53 in DLBCL cells significantly reduced the cytotoxicity of selinexor, especially significant in HGBCL-DH cell lines. Selinexor promoted more significant apoptosis in Wt-TP53 HGBCL-DH cells than in Mut-TP53/p53-expressing HGBCL-DH cells. d INCB057643 and selinexor were cooperative in reducing cell viability and inducing apoptosis in HGBCL-DH cells with Wt-TP53 or Mut-TP53/p53+

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Source: PubMed

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