Mcl-1 is critical for survival in a subgroup of non-small-cell lung cancer cell lines

Zhang, H; Guttikonda, Sudha R; Roberts, Lisa; Uziel, Tamar; Semizarov, Dimitri; Elmore, Steve W.; Leverson, J D; Lam, Lloyd T.

doi:10.1038/onc.2010.559

Cited by 146 publications

(148 citation statements)

References 25 publications

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“…Although the mRNA expression of any single antiapoptotic factor was not predictive of susceptibility to MCL-1 siRNA, the ratio of MCL-1 to BCL-X L mRNA was. Overexpression of BCL-X L , but not BCL-2, conferred significant resistance to MCL-1 siRNA in the MCL-1-dependent cell line SKBR3, validating this correlative analysis and confirming similar findings reported in NSCLC (39). Moreover, gene-silencing experiments confirm that synergy between loss in MCL-1 function and navitoclax is BCL-X L driven.…”

Section: Discussionsupporting

confidence: 77%

MCL-1 Is a Key Determinant of Breast Cancer Cell Survival: Validation of MCL-1 Dependency Utilizing a Highly Selective Small Molecule Inhibitor

Xiao

Nimmer

Sheppard

et al. 2015

Molecular Cancer Therapeutics

104

116

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Hyperexpression of antiapoptotic BCL-2 family proteins allows cells to survive despite the receipt of signals that would ordinarily induce their deletion, a facet frequently exploited by tumors. Tumors addicted to the BCL-2 family proteins for survival are now being targeted therapeutically. For example, navitoclax, a BCL-2/ BCL-X L /BCL-W inhibitor, is currently in phase I/II clinical trials in numerous malignancies. However, the related family member, MCL-1, limits the efficacy of navitoclax and other chemotherapeutic agents. In the present study, we identify breast cancer cell lines that depend upon MCL-1 for survival and subsequently determine the mechanism of apoptosis mediated by the MCL-1 selective inhibitor A-1210477. We demonstrate that apoptosis resulting from a loss in MCL-1 function requires expression of the proapoptotic protein BAK. However, expression of BCL-X L can limit apoptosis resulting from loss in MCL-1 function through sequestration of free BIM. Finally, we demonstrate substantial synergy between navitoclax and MCL-1 siRNA, the direct MCL-1 inhibitor A-1210477, or the indirect MCL-1 inhibitor flavopiridol, highlighting the therapeutic potential for inhibiting BCL-X L and MCL-1 in breast cancer.

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Section: Discussionsupporting

confidence: 77%

MCL-1 Is a Key Determinant of Breast Cancer Cell Survival: Validation of MCL-1 Dependency Utilizing a Highly Selective Small Molecule Inhibitor

Xiao

Nimmer

Sheppard

et al. 2015

Molecular Cancer Therapeutics

104

116

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“…To assess the ability of these inhibitors to induce apoptosis in an MCL-1-dependent system, we used H23 cells, a non-small cell lung carcinoma line that expresses no BCL-2, barely detectable amounts of BCL-X L and depend solely on MCL-1 for survival. 14 None of the putative MCL-1 inhibitors induced apoptosis at early times (4 h), with the possible exception of BI97C1 (Figure 6a). However, after longer exposure (24 h), ABT-263, BI97C1 and TW-37 induced significant apoptosis, whereas BI112D1 and MIM-1 showed little or no activity (Figure 6a).…”

Section: Resultsmentioning

confidence: 95%

“…To confirm and extend these findings to another cellular system, we used H1299 cells, which are dependent for survival on BCL-X L and MCL-1. 14,30 To render the survival of these cells dependent solely on MCL-1, a low concentration of ABT-737 (1 mM) was used to inhibit BCL-X L . Silencing of MCL-1 using RNA interference Figure 6b).…”

Section: Resultsmentioning

confidence: 99%

“…The BCL-2-specific inhibitors, ABT-263 and ABT-199, are ineffective against other anti-apoptotic BCL-2 family members, such as MCL-1 and BCL2A1, which are often associated with chemoresistance. 7,[12][13][14] Many attempts have been made to inhibit MCL-1 by alteration of its transcriptional, translational or post-translational regulatory mechanisms. 12,13,31 In this study, we have evaluated the specificity of putative MCL-1 inhibitors to inhibit MCL-1.…”

Section: Discussionmentioning

confidence: 99%

“…Of the different BCL-2 family members, MCL-1 is commonly amplified in human tumours and is often associated with tumour relapse and chemoresistance, particularly to ABT-737 and ABT-263. 7,[11][12][13][14] These findings highlight an urgent need to find either specific MCL-1 inhibitors or pan-BCL-2 family inhibitors, which could be valuable in treating resistant tumours.…”

mentioning

confidence: 99%

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Evaluation and critical assessment of putative MCL-1 inhibitors

et al. 2013

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High levels of BCL-2 family proteins are implicated in a failed/ineffective apoptotic programme, often resulting in diseases, including cancer. Owing to their potential as drug targets in cancer therapy, several inhibitors of BCL-2 family proteins have been developed. These primarily target specific members of the BCL-2 family, particularly BCL-2 and BCL-X L but are ineffective against MCL-1. Major efforts have been invested in developing inhibitors of MCL-1, which is commonly amplified in human tumours and associated with tumour relapse and chemoresistance. In this report, the specificity of several BCL-2 family inhibitors (ABT-263, UCB-1350883, apogossypol and BH3I-1) was investigated and compared with putative MCL-1 inhibitors designed to exhibit improved or selective binding affinities for MCL-1 (TW-37, BI97C1, BI97C10, BI112D1, compounds 6 and 7, and MCL-1 inhibitor molecule (MIM-1)). ABT-263, BI97C1, BI112D1, MIM-1 and TW-37 exhibited specificity in inducing apoptosis in a Bax/Bak-and caspase-9-dependent manner, whereas the other agents showed no killing activity, or little or no specificity. Of these inhibitors, only ABT-263 and UCB-1350883 induced apoptosis in a BCL-2-or BCL-X L -dependent system. In cells that depend on MCL-1 for survival, ABT-263 and TW-37 induced extensive apoptosis, suggesting that at high concentrations these inhibitors have the propensity to inhibit MCL-1 in a cellular context. TW-37 induced apoptosis, assessed by chromatin condensation, caspase processing and phosphatidylserine externalisation, in a BAK-dependent manner and in cells that require MCL-1 for survival. TW-37-mediated apoptosis was also partly dependent on NOXA, suggesting that derivatives of TW-37, if engineered to exhibit better selectivity and efficacy at low nanomolar concentrations, may provide useful lead compounds for further synthetic programmes. Expanded medicinal chemistry iteration, as performed for the ABT series, may likewise improve the potency and specificity of the evaluated MCL-1 inhibitors.

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Principles for Understanding Mechanisms of Cell Death and Their Role in Cancer Biology

Diepstraten

Marca

and

2023

Precision Cancer Therapies, Volume 1 ‐ Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies

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Mcl-1 is critical for survival in a subgroup of non-small-cell lung cancer cell lines

Cited by 146 publications

References 25 publications

MCL-1 Is a Key Determinant of Breast Cancer Cell Survival: Validation of MCL-1 Dependency Utilizing a Highly Selective Small Molecule Inhibitor

MCL-1 Is a Key Determinant of Breast Cancer Cell Survival: Validation of MCL-1 Dependency Utilizing a Highly Selective Small Molecule Inhibitor

Evaluation and critical assessment of putative MCL-1 inhibitors

Principles for Understanding Mechanisms of Cell Death and Their Role in Cancer Biology

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