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Hyperphosphorylation of BCL-2 family proteins underlies functional resistance to venetoclax in lymphoid malignancies.

  • Chong, Stephen
  • Zhu, Fen
  • Dashevsky, Olga
  • Mizuno, Rin
  • Lai, Jolin
  • Hackett, Liam
  • Ryan, Christine
  • Collins, Mary
  • Iorgulescu, J
  • Guièze, Romain
  • Penailillo, Johany
  • Carrasco, Ruben
  • Hwang, Yeonjoo
  • Muñoz, Denise
  • Lim, Yaw
  • Wu, Catherine
  • Allan, John
  • Furman, Richard
  • Goh, Boon
  • Pervaiz, Shazib
  • And 4 more
Publication Date
Nov 15, 2023
eScholarship - University of California
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The B cell leukemia/lymphoma 2 (BCL-2) inhibitor venetoclax is effective in chronic lymphocytic leukemia (CLL); however, resistance may develop over time. Other lymphoid malignancies such as diffuse large B cell lymphoma (DLBCL) are frequently intrinsically resistant to venetoclax. Although genomic resistance mechanisms such as BCL2 mutations have been described, this probably only explains a subset of resistant cases. Using 2 complementary functional precision medicine techniques - BH3 profiling and high-throughput kinase activity mapping - we found that hyperphosphorylation of BCL-2 family proteins, including antiapoptotic myeloid leukemia 1 (MCL-1) and BCL-2 and proapoptotic BCL-2 agonist of cell death (BAD) and BCL-2 associated X, apoptosis regulator (BAX), underlies functional mechanisms of both intrinsic and acquired resistance to venetoclax in CLL and DLBCL. Additionally, we provide evidence that antiapoptotic BCL-2 family protein phosphorylation altered the apoptotic protein interactome, thereby changing the profile of functional dependence on these prosurvival proteins. Targeting BCL-2 family protein phosphorylation with phosphatase-activating drugs rewired these dependencies, thus restoring sensitivity to venetoclax in a panel of venetoclax-resistant lymphoid cell lines, a resistant mouse model, and in paired patient samples before venetoclax treatment and at the time of progression.

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