Mcl-1 Phosphorylation Defines ABT-737 Resistance That Can Be Overcome by Increased NOXA Expression in Leukemic B cells

Mazumder, Suparna; Choudhary, Gaurav S.; Al-harbi, Sayer; Almasan, Alexandru

doi:10.1158/0008-5472.can-11-4106

Cited by 96 publications

(116 citation statements)

References 46 publications

(65 reference statements)

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“…However, this report did not identify molecular changes underlying the abnormal expression. Konopleva et al and Mazumder et al 46,47 reported that phosphorylation of BCL2 or increased levels of MCL1 impeded ABT-737-induced apoptosis in cancer cells, which could be restored upon inhibition of BCL2 phosphorylation and reduction of MCL1 expression. Again, these manuscripts did not report mutations in BCL2-family proteins associated with ABT-737 resistance.…”

Section: Discussionmentioning

confidence: 99%

Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma

Fresquet

Rieger

Carolis

et al. 2014

Blood

165

133

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Key Points• Acquired selective mutations in Bcl2 and BAX conferred resistance to in experimental models of lymphoma.• Monitoring the potential development of such mutations in patients treated with ABT-199 is advised.Acquired resistance to targeted drugs is emerging as an obstacle to successful cancer treatment. Recently, a BCL2-selective BH3 mimetic termed ABT-199 showed promising therapeutic results in BCL2-dependent tumors. Based on its high affinity for BCL2, we studied potential mechanisms conferring resistance upon ABT-199 therapy, aiming to anticipate its occurrence in the clinic. Two models of resistant lymphomas were established by continuous ABT-199 exposure. In resistant Bcl2-expressing mouse lymphoma cells, 2 missense mutations within the Bcl2 BH3 domain were identified. Both F101C and F101L mutations impeded binding to the BH3 domain, therefore suppressing mitochondrial apoptosis. In resistant human lymphoma cells, a missense mutation in the C-terminal transmembrane domain of proapoptotic BAX (G179E) was found, which abrogated BAX anchoring to mitochondria and blocked ABT-199-induced apoptosis both in vitro and in vivo. Importantly, G179E BAX mutation also induced partial cross-resistance to other antineoplastic drugs. Our study reveals the acquisition of mutations in BCL2 family proteins as a novel mechanism of apoptosis resistance in cancer. These results anticipate the potential development of such mutations in patients treated with , providing a basis to preventing their occurrence and to designing drugs able to circumvent the acquired resistance. (Blood. 2014;123(26):4111-4119) IntroductionThe BCL2 family of proteins, which comprise prosurvival members such as BCL2, BCL-XL, BCL-W, MCL1, and BFL1, proapoptotic BH3-only proteins such as BIM and BAD, and the proapoptotic final effectors BAK and BAX, are critical regulators of the mitochondrial apoptotic pathway. [1][2][3] The development of drugs that inhibit the interaction between antiapoptotic BCL2 family members and BH3-only proteins is having a major impact on cancer therapy. [4][5][6][7] Among them, the BH3 mimetic ABT-737 was highly effective by inducing apoptosis through BCL2, BCL-XL, and BCL-W targeting in solid tumors and hematologic malignancies overexpressing BCL2. 8 Its efficacy, however, was largely diminished in tumors expressing high levels of MCL1, BFL1 and BCL-XL, or in cancer cells lacking BAK and BAX. [9][10][11] Despite the promising preclinical therapeutic efficacy of ABT-263, which is the orally available analog of ABT-737, phase II clinical trials showed a rapid, dose-dependent thrombocytopenia due to the inhibition of BCL-XL, limiting the ability to achieve drug concentrations at an efficacious range in cancer patients.12-14 By reengineering of ABT-263, a potent and high-affinity BCL2-selective BH3 mimetic with low avidity for BCL-XL, termed ABT-199, has been developed. 15 In vitro, ABT-199 inhibited the growth of BCL2-expressing leukemia, lymphoma, and myeloma cell lines more effectively than ABT-737. 15 Additionally, a...

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Section: Discussionmentioning

confidence: 99%

Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma

Fresquet

Rieger

Carolis

et al. 2014

Blood

165

133

View full text Add to dashboard Cite

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“…26 MCL-1/BIM complex, and then the freed BIM induces apoptosis through BAX activation. 27 Other therapeutics, including proteasome inhibitors, may act similarly by activating the endoplasmic reticulum-specific transcription factors ATF3 and ATF4 that regulate NOXA expression. 28,29 Determining the dependence on a particular antiapoptotic BCL-2 family protein has become critical for deciding a personalized therapy.…”

Section: Development Of Bh3 Mimetic Drugsmentioning

confidence: 99%

Development of venetoclax for therapy of lymphoid malignancies

Zhu

Almasan

2017

DDDT

Self Cite

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B-cell lymphoma-2 (BCL-2) family dysfunction and impairment of apoptosis are common in most B-cell lymphoid malignancies. Venetoclax (Venclexta™, formerly ABT-199, GDC-0199) is a highly selective BCL-2 inhibitor, which mimics its BCL-2 homology 3-domain to induce apoptosis. It was approved for treatment of previously treated chronic lymphocytic leukemia (CLL) patients with 17p deletion early in 2016. It has also been in clinical trials for other B-cell lymphoid malignancies. Unlike the other recently approved targeted agents idelalisib and ibrutinib, so far there has been no relapse reported in some patients. Also, unlike the other targeted agents, it is effective against tumor cells that reside in the blood marrow. Despite its promising outcome in CLL, preclinical data have already uncovered mechanistic insights underlying venetoclax resistance, such as upregulation of MCL-1 or BCL-xL expression and protective signaling from the microenvironment. In this review, we describe the role of the BCL-2 family in the pathogenesis of B-cell lymphoid malignancies, the development of venetoclax, and its current clinical outcome in CLL and other B-cell malignancies. We also discuss the resistance mechanisms that develop following venetoclax therapy, potential strategies to overcome them, and how this knowledge can be translated into clinical applications.

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“…24 The emergence of Bcl-2 inhibitors such as ABT-263 and ABT-199 are showing considerable promise for the treatment of CLL, however these drugs are unable to inhibit the antiapoptotic effects of Mcl-1 conferred by the microenvironment, 25 thus identifying a known mechanism of resistance to these BH3-mimetics. [26][27][28][29] Several pan-Bcl-2 family inhibitors such as obatoclax, sabutoclax and AT-101 have been developed with low micromolar potency against Mcl-1. Obatoclax (a BH-3 mimetic) has been investigated in a phase I clinical trial for advanced CLL, but its effect was limited.…”

Section: Introductionmentioning

confidence: 99%

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

et al. 2015

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The pro-survival Bcl-2 family member Mcl-1 is expressed in chronic lymphocytic leukemia (CLL), with high expression correlated with progressive disease. The spliceosome inhibitor spliceostatin A (SSA), is known to regulate Mcl-1 and so here we assessed the ability of SSA to elicit apoptosis in CLL. SSA induced apoptosis of CLL cells at low nanomolar concentrations in a dose-and time-dependent manner, but independently of SF3B1 mutational status, IGHV status and CD38 or ZAP70 expression.However, normal B and T cells were less sensitive than CLL cells (p=0.006 and p<0.001, respectively).

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Mcl-1 Phosphorylation Defines ABT-737 Resistance That Can Be Overcome by Increased NOXA Expression in Leukemic B cells

Cited by 96 publications

References 46 publications

Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma

Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma

Development of venetoclax for therapy of lymphoid malignancies

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

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