ABT-737 Induces Apoptosis in Mantle Cell Lymphoma Cells with a Bcl-2<i>high</i>/Mcl-1<i>low</i> Profile and Synergizes with Other Antineoplastic Agents

Touzeau, Cyrille; Dousset, Christelle; Bodet, Linda; Gomez‐Bougie, Patricia; Bonnaud, Stéphanie; Moreau, Anne; Moreau, Philippe; Pellat‐Deceunynck, Catherine; Amiot, Martine; Gouill, Steven Le

doi:10.1158/1078-0432.ccr-11-0955

Cited by 51 publications

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References 41 publications

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“…Overall, the development of similar mutations has not been demonstrated for proapoptotic drugs targeting BCL2. 1,6,9,13,[48][49][50] Here, we have attempted to elucidate the molecular basis of the acquired resistance to the BH3 mimetic ABT-199, which may be expected based on its high affinity for BCL2. Our study shows the acquisition of Bcl2 and BAX mutations as mechanisms of resistance to ABT-199 in experimental models of lymphoma (Figure 4).…”

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

162

125

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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

162

125

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“…17 Aberrant expression of the BCL-2 protein is also found in MCL and multiple myeloma (MM), where it was associated with deregulation of cyclin D1 (CCND1) expression caused by its translocation. 18,19 For all these reasons, targeting the BCL-2 protein to induce apoptosis is considered to be a promising therapeutic approach in B-cell lymphoid malignancies. While B-cell malignancies, such as CLL and FL, rely on BCL-2, and are therefore designated as BCL-2 dependent, there are others, such as MM, that are more dependent on MCL-1 or both MCL-1 and BCL-xL.…”

Section: Aberrant Expression Of Bcl-2 Protein In B-cell Malignanciesmentioning

confidence: 99%

Development of venetoclax for therapy of lymphoid malignancies

Zhu

Almasan

2017

DDDT

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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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“…For example, in addition to loss of the proapoptotic BH3-only protein BIM, overexpression of antiapoptotic BCL-2 family members is also common. [7][8][9][10] High-level expression of BCL-2, BCL-X L , and MCL-1 has been documented in a variety of MCL cell lines. [7][8][9][10] Moreover, in primary specimens, BCL-2 overexpression is seen in almost 97% of cases, 11 with 15% showing specific genomic gains or amplifications at the BCL-2 locus.…”

Section: Introductionmentioning

confidence: 99%

“…[7][8][9][10] High-level expression of BCL-2, BCL-X L , and MCL-1 has been documented in a variety of MCL cell lines. [7][8][9][10] Moreover, in primary specimens, BCL-2 overexpression is seen in almost 97% of cases, 11 with 15% showing specific genomic gains or amplifications at the BCL-2 locus. 12 Overexpression of BCL-X L has also been reported in MCL cells and linked to constitutive activation of the nuclear factor-kB pathway.…”

Section: Introductionmentioning

confidence: 99%

Mantle cell lymphoma in cyclin D1 transgenic mice with Bim-deficient B cells

Katz

LaBelle

Meng

et al. 2014

Blood

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Mantle cell lymphoma (MCL) is a highly aggressive B-cell lymphoma resistant to conventional chemotherapy. Although defined by the characteristic t(11;14) translocation, MCL has not been recapitulated in transgenic mouse models of cyclin D1 overexpression alone. Indeed, several genetic aberrations have been identified in MCL that may contribute to its pathogenesis and chemoresistance. Of particular interest is the frequent biallelic deletion of the proapoptotic BCL-2 family protein BIM. BIM exerts its pro-death function via its a-helical BH3 death domain that has the dual capacity to inhibit antiapoptotic proteins such as BCL-2 and MCL-1 and directly trigger proapoptotic proteins such as the mitochondrial executioner protein BAX. To evaluate a functional role for Bim deletion in the pathogenesis of MCL, we generated cyclin D1-transgenic mice harboring Bim-deficient B cells. In response to immunization, Em

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ABT-737 Induces Apoptosis in Mantle Cell Lymphoma Cells with a Bcl-2high/Mcl-1low Profile and Synergizes with Other Antineoplastic Agents

Cited by 51 publications

References 41 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

Mantle cell lymphoma in cyclin D1 transgenic mice with Bim-deficient B cells

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