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A Novel BCL-2 Inhibitor APG-2575 Exerts Synthetic Lethality With BTK or MDM2-p53 Inhibitor in Diffuse Large B-Cell

Qiuyun Luo1, Wentao Pan1, Suna Zhou1

  • 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouP.R. China.

Oncology Research
|February 26, 2020
PubMed

Insights

Novel BCL-2 inhibitor APG-2575 shows promise for diffuse large B-cell lymphoma (DLBCL). Combinations with BTK or MDM2p53 inhibitors offer effective therapeutic strategies for relapsed DLBCL.

Area of Science:

  • Oncology
  • Hematology
  • Molecular Biology

Background:

  • Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) presents significant treatment challenges.
  • Key pathogenic factors include apoptosis evasion via BCL-2 family proteins and p53 inactivation, alongside aberrant B-cell receptor signaling.
  • Targeting these pathways offers potential therapeutic avenues for DLBCL.

Purpose of the Study:

  • To explore rational combination therapies for DLBCL targeting BCL-2, Bruton's tyrosine kinase (BTK), or p53 pathways.
  • To evaluate the efficacy of a novel BCL-2 inhibitor, APG-2575, alone and in combination for DLBCL treatment.

Main Methods:

  • In vitro and in vivo studies utilizing APG-2575, ibrutinib (BTK inhibitor), and APG-115 (MDM2p53 inhibitor).
  • Assessment of apoptosis activation, protein expression levels (BIM, MCL-1, p-Akt), and antitumor effects in DLBCL models.
  • Evaluation of survival benefits in animal models.

Main Results:

  • APG-2575 demonstrated efficacy in DLBCL with high BCL-2 expression by activating mitochondrial apoptosis.
  • Combination of ibrutinib with BCL-2 inhibitors showed synergistic effects, upregulating BIM and modulating MCL-1 and p-Akt.
  • APG-2575 combined with APG-115 exhibited strong synergistic effects in p53 wild-type DLBCL, prolonging survival in animal models.

Conclusions:

  • Rational combinations of BCL-2 inhibitors with BTK or MDM2p53 inhibitors represent a precise and effective therapeutic strategy for DLBCL.
  • These findings warrant further clinical investigation for treating relapsed or refractory DLBCL.

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