Discovery and biological evaluation of a potent small molecule CRM1 inhibitor for its selective ablation of extranodal NK/T cell lymphoma
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Curated by eLife
eLife assessment
This study reports a valuable finding on the discovery and evaluation of a potent small molecule inhibitor for CRM1 that may be important to treat extranodal NK/T cell lympohma (ENKTL). The evidence supporting the claims of the authors is solid that reflects an important finding for novel CRM1 inhibitors to treat ENKTL, although additional experimental evidence is needed. The work will be of interest to cancer biologists working on ENKTL.
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Abstract
The overactivation of NF-κB signaling is a key hallmark for the pathogenesis of extranodal natural killer/T cell lymphoma (ENKTL), a very aggressive subtype of non-Hodgkin’s lymphoma yet with rather limited control strategies. Previously, we found that the dysregulated exportin-1 (also known as CRM1) is mainly responsible for tumor cells to evade apoptosis and promote tumor-associated pathways such as NF-κB signaling.
Methods:
Herein we reported the discovery and biological evaluation of a potent small molecule CRM1 inhibitor, LFS-1107. We validated that CRM1 is a major cellular target of LFS-1107 by biolayer interferometry assay (BLI) and the knockdown of CRM1 conferred tumor cells with resistance to LFS-1107.
Results:
We found that LFS-1107 can strongly suppresses the growth of ENKTL cells at low-range nanomolar concentration yet with minimal effects on human platelets and healthy peripheral blood mononuclear cells. Treatment of ENKTL cells with LFS-1107 resulted in the nuclear retention of IkB α and consequent strong suppression of NF-κB transcriptional activities, NF-κB target genes downregulation and attenuated tumor cell growth and proliferation. Furthermore, LFS-1107 exhibited potent activities when administered to immunodeficient mice engrafted with human ENKTL cells.
Conclusions:
Therefore, LFS-1107 holds great promise for the treatment of ENKTL and may warrant translation for use in clinical trials.
Funding:
Yang's laboratory was supported by the National Natural Science Foundation of China (Grant: 81874301), the Fundamental Research Funds for Central University (Grant: DUT22YG122) and the Key Research project of 'be Recruited and be in Command' in Liaoning Province (Personal Target Discovery for Metabolic Diseases).
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Author Response
Reviewer #1 (Public Review):
The current manuscript by Liu et al entitled "Discovery and biological evaluation of a potent small molecule CRM1 inhibitor for its selective ablation of extranodal NK/T cell lymphoma" reports the identification of a novel CRM1 inhibitor and shows its efficiency against extranodal natural killer/T cell lymphoma cells (ENKTL).
This is a very timely and very original study with potential impact in a variety of pathologies not only in ENKTL. However, the main conclusions of the work are not supported by experimental evidence.
Many thanks for your very kind words about our work. We are excited to hear that you think our manuscript is original with considerable translational impact to the field. We are grateful for your valuable time and efforts you have spent to provide your very insightful …
Author Response
Reviewer #1 (Public Review):
The current manuscript by Liu et al entitled "Discovery and biological evaluation of a potent small molecule CRM1 inhibitor for its selective ablation of extranodal NK/T cell lymphoma" reports the identification of a novel CRM1 inhibitor and shows its efficiency against extranodal natural killer/T cell lymphoma cells (ENKTL).
This is a very timely and very original study with potential impact in a variety of pathologies not only in ENKTL. However, the main conclusions of the work are not supported by experimental evidence.
Many thanks for your very kind words about our work. We are excited to hear that you think our manuscript is original with considerable translational impact to the field. We are grateful for your valuable time and efforts you have spent to provide your very insightful comments, which are of great help for our revision.
The study claims that LFS-1107 reversibly inhibits the nuclear export receptor CRM1 but the authors only show that the compound binds to CRM1 and that the CRM1 substrate IκBα accumulates in the cell nucleus upon LFS-1107 treatment. The evidence is indirect and alternative scenarios are certainly possible.
Many thanks for this critical comment. We have conducted extra experiments to demonstrate that LFS-1107 can reversibly inhibit the nuclear transport machinery mediated by CRM1. Namely, culturing the medium for two hours after LFS-1107 treatment restored the transport of IκBα from the nucleus to the cytoplasm. Please see Figure 2 -Figure Supplement 3 for more details.
On the other hand, the manuscript is not always well-written and insufficiently referenced.
Thanks for this critical comment. This has been fixed. We have checked through the manuscript with extensive language editing. Moreover, we have added more references to the manuscript.
The nuclear translocation in figure 2G is not convincing. The western blot in figure 2G shows that LFS-1107 treatment induces IκBα expression, and both cytoplasmic and nuclear amounts increase in a dose-dependent manner. Together, these data do not support nuclear IκBα accumulation upon LFS-1107 treatment.
Thanks for this critical comment. This has been fixed. We have reconducted the Western experiments and our results revealed that only nuclear IκBα amount was increased upon the treatment of LFS-1107. In contrast, cytoplasmic IκBα amount was decreased after the treatment of LFS-1107. Please see Figure 2J for more details.
Reviewer #2 (Public Review):
Indeed, ENKTL is a rather deadly tumor with unmet medical needs. The work is novel in the sense that they designed and identified a very potent inhibitor homing at CRM1 via a deep-reinforcement learning model to suppress the overactivation of NF-κB signaling, an underlying mechanism of ENKTL pathogenesis. The authors demonstrated that LFS-1107 binds more strongly with CRM1 (approximately 40-fold) as compared to KPT-330, an existing CRM1 inhibitor. Another merit of the small-molecule inhibitor is that LFS-1107 can selectively eliminate ENKTL cells while sparing normal blood cells. Their animal results clearly demonstrated that the small-molecule inhibitor was able to extend mouse survival and eliminate tumor cells considerably. Overall, the manuscript may provide a possible therapeutic strategy to treat ENKTL with a good safety profile. The manuscript is also well-written. The weakness of the manuscript is that some details for the design and evaluation of the small-molecular inhibitor are missing.
We are truly grateful for your very kind words about our work. It is very encouraging to know that you think our work is relatively novel and of significance for the field. We sincerely appreciate the valuable time and kind efforts that you have spent on the thorough review of our manuscript.
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eLife assessment
This study reports a valuable finding on the discovery and evaluation of a potent small molecule inhibitor for CRM1 that may be important to treat extranodal NK/T cell lympohma (ENKTL). The evidence supporting the claims of the authors is solid that reflects an important finding for novel CRM1 inhibitors to treat ENKTL, although additional experimental evidence is needed. The work will be of interest to cancer biologists working on ENKTL.
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Reviewer #1 (Public Review):
The current manuscript by Liu et al entitled "Discovery and biological evaluation of a potent small molecule CRM1 inhibitor for its selective ablation of extranodal NK/T cell lymphoma" reports the identification of a novel CRM1 inhibitor and shows its efficiency against extranodal natural killer/T cell lymphoma cells (ENKTL).
This is a very timely and very original study with potential impact in a variety of pathologies not only in ENKTL. However, the main conclusions of the work are not supported by experimental evidence. The study claims that LFS-1107 reversibly inhibits the nuclear export receptor CRM1 but the authors only show that the compound binds to CRM1 and that the CRM1 substrate IκBα accumulates in the cell nucleus upon LFS-1107 treatment. The evidence is indirect and alternative scenarios are …
Reviewer #1 (Public Review):
The current manuscript by Liu et al entitled "Discovery and biological evaluation of a potent small molecule CRM1 inhibitor for its selective ablation of extranodal NK/T cell lymphoma" reports the identification of a novel CRM1 inhibitor and shows its efficiency against extranodal natural killer/T cell lymphoma cells (ENKTL).
This is a very timely and very original study with potential impact in a variety of pathologies not only in ENKTL. However, the main conclusions of the work are not supported by experimental evidence. The study claims that LFS-1107 reversibly inhibits the nuclear export receptor CRM1 but the authors only show that the compound binds to CRM1 and that the CRM1 substrate IκBα accumulates in the cell nucleus upon LFS-1107 treatment. The evidence is indirect and alternative scenarios are certainly possible. On the other hand, the manuscript is not always well-written and insufficiently referenced. The quality of the images is poor. The figure legends are incomplete. The nuclear translocation in figure 2G is not convincing. The western blot in figure 2G shows that LFS-1107 treatment induces IκBα expression, and both cytoplasmic and nuclear amounts increase in a dose-dependent manner. Together, these data do not support nuclear IκBα accumulation upon LFS-1107 treatment.
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Reviewer #2 (Public Review):
Indeed, ENKTL is a rather deadly tumor with unmet medical needs. The work is novel in the sense that they designed and identified a very potent inhibitor homing at CRM1 via a deep-reinforcement learning model to suppress the overactivation of NF-κB signaling, an underlying mechanism of ENKTL pathogenesis. The authors demonstrated that LFS-1107 binds more strongly with CRM1 (approximately 40-fold) as compared to KPT-330, an existing CRM1 inhibitor. Another merit of the small-molecule inhibitor is that LFS-1107 can selectively eliminate ENKTL cells while sparing normal blood cells. Their animal results clearly demonstrated that the small-molecule inhibitor was able to extend mouse survival and eliminate tumor cells considerably. Overall, the manuscript may provide a possible therapeutic strategy to treat ENKTL …
Reviewer #2 (Public Review):
Indeed, ENKTL is a rather deadly tumor with unmet medical needs. The work is novel in the sense that they designed and identified a very potent inhibitor homing at CRM1 via a deep-reinforcement learning model to suppress the overactivation of NF-κB signaling, an underlying mechanism of ENKTL pathogenesis. The authors demonstrated that LFS-1107 binds more strongly with CRM1 (approximately 40-fold) as compared to KPT-330, an existing CRM1 inhibitor. Another merit of the small-molecule inhibitor is that LFS-1107 can selectively eliminate ENKTL cells while sparing normal blood cells. Their animal results clearly demonstrated that the small-molecule inhibitor was able to extend mouse survival and eliminate tumor cells considerably. Overall, the manuscript may provide a possible therapeutic strategy to treat ENKTL with a good safety profile. The manuscript is also well-written. The weakness of the manuscript is that some details for the design and evaluation of the small-molecular inhibitor are missing.
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