Identification of Expression Signatures Predictive of Sensitivity to the Bcl-2 Family Member Inhibitor ABT-263 in Small Cell Lung Carcinoma and Leukemia/Lymphoma Cell Lines

Tahir, Stephen K.; Wass, John; Joseph, Mary K.; Devanarayan, Viswanath; Hessler, Paul; Zhang, Haichao; Elmore, Steve W.; Kroeger, Paul E.; Tse, Christin; Rosenberg, Saul H.; Anderson, Mark G.

doi:10.1158/1535-7163.mct-09-0651

Cited by 65 publications

(60 citation statements)

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“…Bcl‐xl and Bcl‐2 increased in HUVECs, IMR90 cells, and MEFs but not preadipocytes, suggesting that senescent HUVECs, IMR90 cells, and MEFs might depend more on this pro‐survival pathway than N‐resistant preadipocytes. Consistent with this, Bcl‐2 family molecular signatures, including Bcl‐xl, Bcl‐2, Noxa, and Bcl‐w, correctly predict susceptibility to N of 70% of small‐cell lung cancers and 81% of leukemias and lymphomas (Tahir et al ., 2010; Vo et al ., 2012). These same Bcl‐2 family molecular signatures are features of senescent HUVECs, IMR90 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…N is senolytic in HUVECs, IMR90 cells, and MEFs, but not in senescent human primary preadipocytes. Based on these senescent cell type‐specific effects of N and its ability to treat cancers with specific Bcl‐2 family signatures (Tahir et al ., 2010; Vo et al ., 2012), we also tested signatures of Bcl‐2 family member proteins and found these signatures do indeed correlate with susceptibilities of different senescent cell types to N. This suggests that the molecular signatures of different types of senescent cells may be of utility in predicting responsiveness to Bcl‐2 family inhibitors or potentially to other classes of senolytic drugs.…”

Section: Introductionmentioning

confidence: 99%

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Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

et al. 2016

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SummaryClearing senescent cells extends healthspan in mice. Using a hypothesis‐driven bioinformatics‐based approach, we recently identified pro‐survival pathways in human senescent cells that contribute to their resistance to apoptosis. This led to identification of dasatinib (D) and quercetin (Q) as senolytics, agents that target some of these pathways and induce apoptosis preferentially in senescent cells. Among other pro‐survival regulators identified was Bcl‐xl. Here, we tested whether the Bcl‐2 family inhibitors, navitoclax (N) and TW‐37 (T), are senolytic. Like D and Q, N is senolytic in some, but not all types of senescent cells: N reduced viability of senescent human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts, and murine embryonic fibroblasts (MEFs), but not human primary preadipocytes, consistent with our previous finding that Bcl‐xl siRNA is senolytic in HUVECs, but not preadipocytes. In contrast, T had little senolytic activity. N targets Bcl‐2, Bcl‐xl, and Bcl‐w, while T targets Bcl‐2, Bcl‐xl, and Mcl‐1. The combination of Bcl‐2, Bcl‐xl, and Bcl‐w siRNAs was senolytic in HUVECs and IMR90 cells, while combination of Bcl‐2, Bcl‐xl, and Mcl‐1 siRNAs was not. Susceptibility to N correlated with patterns of Bcl‐2 family member proteins in different types of human senescent cells, as has been found in predicting response of cancers to N. Thus, N is senolytic and acts in a potentially predictable cell type‐restricted manner. The hypothesis‐driven, bioinformatics‐based approach we used to discover that dasatinib (D) and quercetin (Q) are senolytic can be extended to increase the repertoire of senolytic drugs, including additional cell type‐specific senolytic agents.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

et al. 2016

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“…Nontreated cells were used as a control. biomarker regardless of both the level of Bcl-2 (12)(13)(14) and the nature of the tumor cell. Indeed, several studies and ours have identified a uniform profile (Bcl-2 high /Mcl-1 low ) for ABT-737-sensitive cells.…”

Section: Discussionmentioning

confidence: 99%

“…The present investigation provides the biological rationale for these future clinical trials to evaluate ABT-737 alone or in combination with Mcl-1-reducing agents in MCL patients. Indeed, ABT-263 (navitoclax; Abbott), which is an orally bioavailable BH3-mimetic compound of the same class as ABT-737 and currently under investigation in hematologic and solid malignancies, could also be used as ABT-737 (13,(43)(44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

“…ABT-737 displaces proapoptotic BH3-only from Bcl-2 or Bcl-xL, leading to activation of Bax and Bak and downstream caspases (9). Because of the low affinity of ABT-737 for Mcl-1, high basal levels of Mcl-1 have been associated with ABT-737 resistance (11)(12)(13)(14). Previous studies have also shown that ABT-737 is effective as a single agent against some leukemia/ lymphoma cell lines both in vitro and in vivo (11,(15)(16)(17).…”

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confidence: 99%

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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

Touzeau

Dousset

Bodet

et al. 2011

Clinical Cancer Research

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Purpose: Mantle cell lymphoma (MCL) is considered to be incurable. ABT-737 is a BH3 mimetic that targets Bcl-2, which is overexpressed in MCL and implicated in drug resistance. The present work investigated the antitumor effect of ABT-737. Experimental Design: Six MCL cell lines and primary MCL cells (n = 13) were used. Sensitivity to ABT-737 was assessed, and expression levels of Bcl-2 and Mcl-1 were analyzed. Finally, ABT-737 was combined with other cytotoxic agents to promote tailored therapy. Results: MINO and GRANTA-519 cell lines were highly sensitive to ABT-737 [the median lethal dose (LD50) = 20 and 80 nmol/L, respectively], whereas other cell lines were resistant. In primary MCL cells, 46% of patients' samples were sensitive to ABT-737. The analysis of protein expression levels revealed that both sensitive cell lines and primary MCL cells could be characterized by a Bcl-2high/Mcl-1low profile, whereas resistant MCL cells contained high levels of Mcl-1. ABT-737 induced a rapid disruption of both Bcl-2/Bax and Bcl-2/Bik complexes. In addition, silencing of Mcl-1 by siRNA sensitized MCL cell lines to ABT-737. Similarly, flavopiridol, which induces Mcl-1 downregulation, in combination with ABT-737 led to a synergistic anti-MCL effect in ABT-737–resistant cell lines. This synergy was also observed when ABT-737 was combined with either bortezomib or cytarabine. Conclusions: The present work shows that ABT-737 induces strong apoptosis in MCL cells expressing a Bcl-2high/Mcl-1low profile. In ABT-737–resistant MCL cells, downregulation of Mcl-1 overcomes Mcl-1–induced resistance and synergizes ABT-737 effects. Our results strongly support the use of ABT-737 according to the Bcl-2/Mcl-1 tumor cell profiles in the treatment of MCL. Clin Cancer Res; 17(18); 5973–81. ©2011 AACR.

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Development of a flow cytometric method for quantification of BCL‐2 family members in chronic lymphocytic leukemia and correlation with sensitivity to BCL‐2 family inhibitors

Smith

Chyla

McKeegan

et al. 2016

Cytometry Part B Clinical

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This method can quantify BCL-2 family members in a specific, highly reproducible and sensitive fashion, and requires fewer cells compared to western blot. It is particularly useful for identifying BCL-2, BCL-X , and MCL-1 protein levels in a specific cell population within a heterogeneous population like those collected from CLL patients. These data show that our QFCM method can be used to facilitate the quantification and evaluation of biomarkers predictive of response in patients treated with BCL-2 family member inhibitors. © 2016 International Clinical Cytometry Society.

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Identification of Expression Signatures Predictive of Sensitivity to the Bcl-2 Family Member Inhibitor ABT-263 in Small Cell Lung Carcinoma and Leukemia/Lymphoma Cell Lines

Cited by 65 publications

References 47 publications

Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

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

Development of a flow cytometric method for quantification of BCL‐2 family members in chronic lymphocytic leukemia and correlation with sensitivity to BCL‐2 family inhibitors

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