BH3 profiling identifies heterogeneous dependency on Bcl-2 family members in multiple myeloma and predicts sensitivity to BH3 mimetics

Touzeau, Cyrille; Ryan, Jeremy; Guerriero, Jennifer L.; Moreau, Philippe; Chonghaile, Tríona Ní; Gouill, Steven Le; Richardson, Paul G.; Anderson, Kenneth C.; Amiot, Martine; Letai, Antony

doi:10.1038/leu.2015.184

Cited by 126 publications

(143 citation statements)

References 19 publications

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“…In addition, a small cluster of patients with leukemia showed sensitivity to combinations of the HDAC inhibitor panobinostat in tandem with the JAK inhibitor ruxolitinib and/or the multikinase inhibitor sorafenib. To confirm that these clusters result from the effectiveness of the combination rather than that of a single agent, IC 50 values for each single agent were mapped according to the combination cluster pattern. Importantly, apart from venetoclax, which, as a single agent, demonstrated potent and selective efficacy in lymphoid (predominantly CLL) patient samples, singleagent efficacies did not align uniquely to a combination efficacyderived myeloid or lymphoid cluster (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To maximize the translational impact of any findings, combinations used FDA-approved drugs if possible. For comparison, cells were also tested against graded concentrations of each inhibitor alone, and sensitivity was assessed by a methanethiosulfonate (MTS)-based viability assay after 3 d. The efficacy of each combination relative to its respective single agents was quantified with combination ratio (CR) values, defined as the IC 50 or area under the fitted doseresponse curve for the combination divided by the lowest IC 50 or area under the curve (AUC) value for either single agent. By this metric, a CR value of less than 1 indicates the drug combination is more effective than either single agent.…”

Section: Resultsmentioning

confidence: 99%

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Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies

Kurtz

Eide

Kaempf

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Translating the genetic and epigenetic heterogeneity underlying human cancers into therapeutic strategies is an ongoing challenge. Large-scale sequencing efforts have uncovered a spectrum of mutations in many hematologic malignancies, including acute myeloid leukemia (AML), suggesting that combinations of agents will be required to treat these diseases effectively. Combinatorial approaches will also be critical for combating the emergence of genetically heterogeneous subclones, rescue signals in the microenvironment, and tumor-intrinsic feedback pathways that all contribute to disease relapse. To identify novel and effective drug combinations, we performed ex vivo sensitivity profiling of 122 primary patient samples from a variety of hematologic malignancies against a panel of 48 drug combinations. The combinations were designed as drug pairs that target nonoverlapping biological pathways and comprise drugs from different classes, preferably with Food and Drug Administration approval. A combination ratio (CR) was derived for each drug pair, and CRs were evaluated with respect to diagnostic categories as well as against genetic, cytogenetic, and cellular phenotypes of specimens from the two largest disease categories: AML and chronic lymphocytic leukemia (CLL). Nearly all tested combinations involving a BCL2 inhibitor showed additional benefit in patients with myeloid malignancies, whereas select combinations involving PI3K, CSF1R, or bromodomain inhibitors showed preferential benefit in lymphoid malignancies. Expanded analyses of patients with AML and CLL revealed specific patterns of ex vivo drug combination efficacy that were associated with select genetic, cytogenetic, and phenotypic disease subsets, warranting further evaluation. These findings highlight the heuristic value of an integrated functional genomic approach to the identification of novel treatment strategies for hematologic malignancies.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies

Kurtz

Eide

Kaempf

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…28,29 Determining the dependence on a particular antiapoptotic BCL-2 family protein has become critical for deciding a personalized therapy. The advent of "BH3 profiling" using specific peptides has led the way, 30,31 although more recent availability of specific small-molecule inhibitors of BCL-xL (Wehi-539, A-1155463, A-1331852) 32,33 and MCL-1 (A-1210477, S63845), 34,35 in addition to inhibition of BCL-2 by venetoclax, has facilitated, at least in an ex vivo culture, a rapid determination of the BCL-2 family protein dependence. These tools make it possible to choose the most effective therapeutics to be used based on a functional output, their ability to induce tumor cell death.…”

Section: Development Of Bh3 Mimetic Drugsmentioning

confidence: 99%

“…These tools make it possible to choose the most effective therapeutics to be used based on a functional output, their ability to induce tumor cell death. 31 A panel of cell lines has been also engineered to facilitate this analysis by faithfully assessing the efficacy of BH3-mimetic small molecules in preclinical mouse models.…”

Section: Development Of Bh3 Mimetic Drugsmentioning

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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“…5 BH3 profiling analysis confirmed a BCL-2 survival dependency for a subgroup of MM cells. 6 Antagonizing BCL-2 function to induce apoptosis is therefore a compelling therapeutic approach in MM. Venetoclax is a potent, selective, orally bioavailable inhibitor of BCL-2.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma

Kumar

Kaufman

Gasparetto

et al. 2017

Blood

400

384

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BH3 profiling identifies heterogeneous dependency on Bcl-2 family members in multiple myeloma and predicts sensitivity to BH3 mimetics

Cited by 126 publications

References 19 publications

Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies

Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies

Development of venetoclax for therapy of lymphoid malignancies

Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma

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