Biomarkers of Therapeutic Response to BCL2 Antagonists in Cancer

Lam, Lloyd T.; Zhang, Haichao; Chyla, Brenda

doi:10.1007/s40291-012-0003-6

Cited by 12 publications

(11 citation statements)

References 99 publications

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“…Others have shown that SCLC cell lines are sensitive to treatment with navitoclax (ABT-263), a dual inhibitor of BCL2 and BCLxl (22). In contrast, other solid tumors were shown to depend mainly on BCLxl and MCL1 but not BCL2 for survival (34). The role of MCL1 in BET inhibitor sensitivity in SCLC cells is currently under investigation.…”

Section: Discussionmentioning

confidence: 99%

Vulnerability of Small-Cell Lung Cancer to Apoptosis Induced by the Combination of BET Bromodomain Proteins and BCL2 Inhibitors

Lam

Lin

Faivre

et al. 2017

Molecular Cancer Therapeutics

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Ten percent to 15% of all lung cancers are small-cell lung cancer (SCLC). SCLC usually grows and metastasizes before it is diagnosed and relapses rapidly upon treatment. Unfortunately, no new targeted agent has been approved in the past 30 years for patients with SCLC. The BET (bromodomain and extraterminal) proteins bind acetylated histones and recruit protein complexes to promote transcription initiation and elongation. BET proteins have been shown to regulate expression of key genes in oncogenesis, such as , and Here, we demonstrate that approximately 50% of SCLC cell lines are exquisitely sensitive to growth inhibition by the BET inhibitor, ABBV-075. The majority of these SCLC cell lines underwent apoptosis in response to ABBV-075 treatment via induction of caspase-3/7 activity. ABBV-075 enhanced the expression of proapoptotic protein BIM and downregulated antiapoptotic proteins BCL2 and BCLxl to a lesser extent. Furthermore, BET inhibition increased BCL2-BIM complex, thus priming the cells for apoptosis. Indeed, strong synergy was observed both and when cotreating the cells with BET inhibitor and the BH3-mimetic, BCL2 inhibitor venetoclax (ABT-199). ABBV-075 interaction with venetoclax positively correlated with BCL2 expression. Taken together, our studies provide a rationale for treating SCLC with BET and BCL2 inhibitors in tumors with high BCL2 protein expression. .

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Section: Discussionmentioning

confidence: 99%

Vulnerability of Small-Cell Lung Cancer to Apoptosis Induced by the Combination of BET Bromodomain Proteins and BCL2 Inhibitors

Lam

Lin

Faivre

et al. 2017

Molecular Cancer Therapeutics

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“…The link between overexpressed anti-apoptotic BCL-2 family proteins and cancer is now well established [4]. Enhanced expression of these proteins has been reported in numerous cancers, which permits cell growth and survival in the presence of apoptotic signals associated with the transformed phenotype, and can also lead to the failure of chemotherapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

Potential mechanisms of resistance to venetoclax and strategies to circumvent it

et al. 2017

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BackgroundVenetoclax (ABT-199), a first-in-class orally bioavailable BCL-2-selective inhibitor, was recently approved by the FDA for use in patients with 17p-deleted chronic lymphocytic leukemia who have received prior therapy. It is also being evaluated in numerous clinical trials for treating patients with various hematologic malignancies. As with any targeted cancer therapy, it is critically important to identify potential mechanisms of resistance, both for patient stratification and developing strategies to overcome resistance, either before it develops or as it emerges.MethodsIn order to gain a more comprehensive insight into the nature of venetoclax resistance mechanisms, we evaluated the changes in the BCL-2 family members at the genetic and expression levels in seven different venetoclax-resistant derived leukemia and lymphoma cell lines.ResultsGene and protein expression analyses identified a number of different alterations in the expression of pro- and anti-apoptotic BCL-2 family members. In the resistant derived cells, an increase in either or both the anti-apoptotic proteins BCL-XL or MCL-1, which are not targeted by venetoclax was observed, and either concomitant or exclusive with a decrease in one or more pro-apoptotic proteins. In addition, mutational analysis also revealed a mutation in the BH3 binding groove (F104L) that could potentially interfere with venetoclax-binding. Not all changes may be causally related to venetoclax resistance and may only be an epiphenomenon. For resistant cell lines showing elevations in BCL-XL or MCL-1, strong synergistic cell killing was observed when venetoclax was combined with either BCL-XL- or MCL-1-selective inhibitors, respectively. This highlights the importance of BCL-XL- and MCL-1 as causally contributing to venetoclax resistance.ConclusionsOverall our study identified numerous changes in multiple resistant lines; the changes were neither mutually exclusive nor universal across the cell lines tested, thus exemplifying the complexity and heterogeneity of potential resistance mechanisms. Identifying and evaluating their contribution has important implications for both patient selection and the rational development of strategies to overcome resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3383-5) contains supplementary material, which is available to authorized users.

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“…The role of anti-apoptotic BCL-2 family proteins in various cancers has been well studied [ 2 ]. BCL-2 was initially identified from the breakpoint of the t(14;18) chromosomal translocation found in over 60 % of indolent B cell non-Hodgkin’s lymphoma [ 3 – 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…BCL-X L has been implicated as a key survival factor in numerous solid tumors [ 2 ]. Based on the evidence that cancer types with BCL2 and MCL1 amplification are more prone to inhibition of their encoded proteins, we hypothesized that cancers with a significant frequency of BCL2L1 amplification are more dependent on BCL-X L for survival.…”

Section: Introductionmentioning

confidence: 99%

Genomic analysis and selective small molecule inhibition identifies BCL-XL as a critical survival factor in a subset of colorectal cancer

et al. 2015

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BackgroundDefects in programmed cell death, or apoptosis, are a hallmark of cancer. The anti-apoptotic B-cell lymphoma 2 (BCL-2) family proteins, including BCL-2, BCL-XL, and MCL-1 have been characterized as key survival factors in multiple cancer types. Because cancer types with BCL2 and MCL1 amplification are more prone to inhibition of their respectively encoded proteins, we hypothesized that cancers with a significant frequency of BCL2L1 amplification would have greater dependency on BCL-XL for survival.MethodsTo identify tumor subtypes that have significant frequency of BCL2L1 amplification, we performed data mining using The Cancer Genome Atlas (TCGA) database. We then assessed the dependency on BCL-XL in a panel of cell lines using a selective and potent BCL-XL inhibitor, A-1155463, and BCL2L1 siRNA. Mechanistic studies on the role of BCL-XL were further undertaken via a variety of genetic manipulations.ResultsWe identified colorectal cancer as having the highest frequency of BCL2L1 amplification across all tumor types examined. Colorectal cancer cell lines with BCL2L1 copy number >3 were more sensitive to A-1155463. Consistently, cell lines with high expression of BCL-XL and NOXA, a pro-apoptotic protein that antagonizes MCL-1 activity were sensitive to A-1155463. Silencing the expression of BCL-XL via siRNA killed the cell lines that were sensitive to A-1155463 while having little effect on lines that were resistant. Furthermore, silencing the expression of MCL-1 in resistant cell lines conferred sensitivity to A-1155463, whereas silencing NOXA abrogated sensitivity.ConclusionsThis work demonstrates the utility of characterizing frequent genomic alterations to identify cancer survival genes. In addition, these studies demonstrate the utility of the highly potent and selective compound A-1155463 for investigating the role of BCL-XL in mediating the survival of specific tumor types, and indicate that BCL-XL inhibition could be an effective treatment for colorectal tumors with high BCL-XL and NOXA expression.

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Biomarkers of Therapeutic Response to BCL2 Antagonists in Cancer

Cited by 12 publications

References 99 publications

Vulnerability of Small-Cell Lung Cancer to Apoptosis Induced by the Combination of BET Bromodomain Proteins and BCL2 Inhibitors

Vulnerability of Small-Cell Lung Cancer to Apoptosis Induced by the Combination of BET Bromodomain Proteins and BCL2 Inhibitors

Potential mechanisms of resistance to venetoclax and strategies to circumvent it

Genomic analysis and selective small molecule inhibition identifies BCL-XL as a critical survival factor in a subset of colorectal cancer

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