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Review
. 2017 Sep;58(9):1-17.
doi: 10.1080/10428194.2017.1283032. Epub 2017 Jan 31.

Pathways and mechanisms of venetoclax resistance

Prithviraj Bose  1 , Varsha Gandhi  1   2 , Marina Konopleva  1
Affiliations
Review

Pathways and mechanisms of venetoclax resistance

VSports - Prithviraj Bose et al. Leuk Lymphoma. 2017 Sep.

Abstract

The approval of venetoclax, a 'BH3-mimetic' antagonist of the BCL-2 anti-apoptotic protein, for chronic lymphocytic leukemia represents a major milestone in translational apoptosis research VSports手机版. Venetoclax has already received 'breakthrough' designation for acute myeloid leukemia, and is being studied in many other tumor types. However, resistance to BCL-2 inhibitor monotherapy may rapidly ensue. Several studies have shown that the other two major anti-apoptotic BCL-2 family proteins, BCL-XL and MCL-1, are the main determinants of resistance to venetoclax. This opens up possibilities for rationally combining venetoclax with other targeted agents to circumvent resistance. Here, we summarize the most promising combinations, and highlight those already in clinical trials. There is also increasing recognition that different tumors display different degrees of addiction to individual BCL-2 family proteins, and of the need to refine current 'BH3 profiling' techniques. Finally, the successful clinical development of potent and selective antagonists of BCL-XL and MCL-1 is eagerly awaited. .

Keywords: BCL-2; BCL-XL; MCL-1; Venetoclax; rational combinations; resistance V体育安卓版. .

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Figures (V体育2025版)

Figure 1
Figure 1
Potential mechanism of action of ABT-199 (venetoclax). Venetoclax binds to the BH3-binding groove of BCL-2 and displaces Bim and other BH3-only proteins that are normally sequestered by this pro-survival (anti-apoptotic) protein. These BH3-only proteins are thus freed to activate the apoptosis effectors, Bax and Bak. Bax/Bak activation then leads to their oligomerization and mitochondrial outer membrane permeabilization. This commits the cell to apoptosis through the mitochondrial pathway, which is triggered by the activation of caspases. Modified, with permission, from ref. [51].
See this image and copyright information in PMC

V体育ios版 - References

    1. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: A multicentre, open-label, phase 2 study. Lancet Oncol. 2016 - PubMed (VSports在线直播)
    1. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:311–22. - PMC - PubMed
    1. Jones J, Choi MY, Mato AR, et al. Venetoclax (VEN) monotherapy for patients with chronic lymphocytic leukemia (CLL) who relapsed after or were refractory to ibrutinib or idelalisib. Blood. 2016;128:637.
    1. Kwok M, Rawstron AC, Varghese A, et al. Minimal residual disease is an independent predictor for 10-year survival in CLL. Blood. 2016;128:2770–3. - PubMed
    1. Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016 - PMC - PubMed

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