Targeting the fatty acid binding proteins disrupts multiple myeloma cell cycle progression and MYC signaling
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This manuscript will be of interest to researchers within the fields of haematological and bone oncology. It reveals a novel effect of FABP5 inhibition to reduce myeloma growth both in vitro and in vivo, with convincing supporting associations between FABP5 expression and survival in patients with myeloma.
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Abstract
Multiple myeloma is an incurable plasma cell malignancy with only a 53% 5-year survival rate. There is a critical need to find new multiple myeloma vulnerabilities and therapeutic avenues. Herein, we identified and explored a novel multiple myeloma target: the fatty acid binding protein (FABP) family. In our work, myeloma cells were treated with FABP inhibitors (BMS3094013 and SBFI-26) and examined in vivo and in vitro for cell cycle state, proliferation, apoptosis, mitochondrial membrane potential, cellular metabolism (oxygen consumption rates and fatty acid oxidation), and DNA methylation properties. Myeloma cell responses to BMS309403, SBFI-26, or both, were also assessed with RNA sequencing (RNA-Seq) and proteomic analysis, and confirmed with western blotting and qRT-PCR. Myeloma cell dependency on FABPs was assessed using the Cancer Dependency Map (DepMap). Finally, MM patient datasets (CoMMpass and GEO) were mined for FABP expression correlations with clinical outcomes. We found that myeloma cells treated with FABPi or with FABP5 knockout (generated via CRISPR/Cas9 editing) exhibited diminished proliferation, increased apoptosis, and metabolic changes in vitro. FABPi had mixed results in vivo, in two pre-clinical MM mouse models, suggesting optimization of in vivo delivery, dosing, or type of FABP inhibitors will be needed before clinical applicability. FABPi negatively impacted mitochondrial respiration and reduced expression of MYC and other key signaling pathways in MM cells in vitro. Clinical data demonstrated worse overall and progression-free survival in patients with high FABP5 expression in tumor cells. Overall, this study establishes the FABP family as a potentially new target in multiple myeloma. In MM cells, FABPs have a multitude of actions and cellular roles that result in the support of myeloma progression. Further research into the FABP family in MM is warrented, especially into the effective translation of targeting these in vivo.
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eLife assessment
This manuscript will be of interest to researchers within the fields of haematological and bone oncology. It reveals a novel effect of FABP5 inhibition to reduce myeloma growth both in vitro and in vivo, with convincing supporting associations between FABP5 expression and survival in patients with myeloma.
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Reviewer #1 (Public Review):
Multiple myeloma (MM) is a common often incurable plasma cell disease. Fatty acid binding proteins (FABPs) represent biomarkers for aggressive disease in MM, and pharmacologically inhibiting FABPs kill tumor cells and induce cell cycle arrest. This work demonstrates that targeting FABP5 holds great therapeutic potential for killing diseased cells, with few negative off-target effects on healthy cells.
The authors first found their FABP target by utilizing the Broad Institute's Cancer Dependency Map (DepMap), where only FABP5 exhibited a score in all 20 MM cell lines that demonstrated a strong reliance on FABP5 for survival. To test the effects of FABP5 in MM cell lines they created knock outs, however, the efficacy was relatively low with expression down only 84%. The results demonstrated a reduced …
Reviewer #1 (Public Review):
Multiple myeloma (MM) is a common often incurable plasma cell disease. Fatty acid binding proteins (FABPs) represent biomarkers for aggressive disease in MM, and pharmacologically inhibiting FABPs kill tumor cells and induce cell cycle arrest. This work demonstrates that targeting FABP5 holds great therapeutic potential for killing diseased cells, with few negative off-target effects on healthy cells.
The authors first found their FABP target by utilizing the Broad Institute's Cancer Dependency Map (DepMap), where only FABP5 exhibited a score in all 20 MM cell lines that demonstrated a strong reliance on FABP5 for survival. To test the effects of FABP5 in MM cell lines they created knock outs, however, the efficacy was relatively low with expression down only 84%. The results demonstrated a reduced proliferation and subsequently, the authors sought to use chemical FABP inhibitors. To understand how FABP5 inhibition could lead to reduced MM cell proliferation, RNAseq was performed. The results analysis demonstrated that MYC, a known oncogene, was found as a central downregulated node. MYC's importance was further confirmed with proteomic analysis.
To help put these findings into clinical context, they investigated the combination of FABP inhibition (FABPi) with dexamethasone, a common therapy for MM patients, where they found that FABPi enhanced dexamethasone's efficacy. Overall, this is an outstanding manuscript that should help advance the overall understanding of MM. The major weakness relates to an unclear mechanism of action (MOA) for FABP5 in MM cells.
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Reviewer #2 (Public Review):
Farrell et al. investigated the effect of FABP5 inhibition in myeloma, demonstrating a reduction in tumour burden. They present extensive data to demonstrate that FABP5 inhibition, either by CRISPR-Cas9 or pharmacologically, reduces myeloma cell growth. Transcriptomic and proteomic profiling reveals a wealth of gene and protein sets that are altered in response to FABP5 inhibition, the most notable of which are the UPR and MYC. Two preclinical murine models of myeloma are employed, with a significant reduction in tumour burden and increase in survival observed in response to FABP5 inhibition, providing strong support for the translational potential of this approach in myeloma. Supporting in silico analysis of patient datasets demonstrates associations between FABP5 expression and myeloma survival, providing …
Reviewer #2 (Public Review):
Farrell et al. investigated the effect of FABP5 inhibition in myeloma, demonstrating a reduction in tumour burden. They present extensive data to demonstrate that FABP5 inhibition, either by CRISPR-Cas9 or pharmacologically, reduces myeloma cell growth. Transcriptomic and proteomic profiling reveals a wealth of gene and protein sets that are altered in response to FABP5 inhibition, the most notable of which are the UPR and MYC. Two preclinical murine models of myeloma are employed, with a significant reduction in tumour burden and increase in survival observed in response to FABP5 inhibition, providing strong support for the translational potential of this approach in myeloma. Supporting in silico analysis of patient datasets demonstrates associations between FABP5 expression and myeloma survival, providing a strong clinical correlate. The conclusions of the paper are well supported by the data.
Strengths
To the best of my knowledge, this is a novel finding in myeloma, revealing a new therapeutic approach which appears to be highly effective in reducing tumour burden. The work is comprehensive, using a panel of myeloma cell lines and a multitude of in vitro approaches to determine response to FABP inhibition.
Weaknesses
FABP inhibition is known to be effective in other cancers, therefore it is not surprising that it is also effective in myeloma. Mechanism is eluded to following the transcriptomic and proteomic analysis, however, this is not explored in a conclusive manner. Myeloma is a cancer of the bone marrow associated with osteolysis, however, no analysis of the effect of FABP inhibition on myeloma bone disease is presented.
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Reviewer #3 (Public Review):
In this manuscript, Farrell and colleagues investigated the role of FABP genes in multiple myeloma progression using a combination of in vitro, in vivo, and in silico approaches, as well as genetic and pharmacologic interventions. They report that FABP genes are expressed in myeloma cells and show that genetic inhibition of FABP5 or pharmacologic inhibition of several FABP genes decreases myeloma cell number in vitro and in vivo. The decrease in cell number correlates with cell cycle arrest and a modest increase in apoptosis. By performing a comprehensive transcriptomic, proteomic, and metabolomic analysis, the authors find that inhibition of FABP genes reduces MYC gene expression and UPR genes, and decreases mitochondrial respiration, and blocks. Consistent with their in vitro and in vivo data, the authors …
Reviewer #3 (Public Review):
In this manuscript, Farrell and colleagues investigated the role of FABP genes in multiple myeloma progression using a combination of in vitro, in vivo, and in silico approaches, as well as genetic and pharmacologic interventions. They report that FABP genes are expressed in myeloma cells and show that genetic inhibition of FABP5 or pharmacologic inhibition of several FABP genes decreases myeloma cell number in vitro and in vivo. The decrease in cell number correlates with cell cycle arrest and a modest increase in apoptosis. By performing a comprehensive transcriptomic, proteomic, and metabolomic analysis, the authors find that inhibition of FABP genes reduces MYC gene expression and UPR genes, and decreases mitochondrial respiration, and blocks. Consistent with their in vitro and in vivo data, the authors show that FAPB5 expression in patients negatively correlates with survival. Overall, the data is interesting and provides new therapeutic targets to combat the growth of myeloma cells in the bone marrow. The conclusions are mostly supported by the data; however some mechanistic aspects of the studies need to be clarified and extended.
Strengths:
- The use of genetic (CRISPR) and pharmacologic (BMS309403 and SBFI-26) and in vitro and in vivo models adds scientific rigor to the findings presented and increase their clinical relevance.
- The authors perform a highly comprehensive analysis of the consequences of FABP inhibition in myeloma cells using transcriptomic, proteomic or metabolic analysis. The bioinformatic analysis of these data is well done and rendered additional potential targets (genes or pathways) mediating FABP effects on myeloma cells.
- The addition of in silico analysis of patient databases adds translational value to their findings.
Weaknesses:
- Despite the comprehensive bioinformatic analysis performed by the authors, the mechanisms by which inhibition of members of the FABP family decreases tumor progression are not investigated. Several potential mechanisms are inferred (i.e., MYC, DNA methylation, UPR genes, mitochondrial respiration) but no experiments are performed to demonstrate their involvement in the response to FABP inhibitors.
- The authors indicate FABP inhibitors are safe, but their toxicity analysis is limited to body weight, which might not be a good indicator of toxicities.
- FABP inhibitors have systemic effects that could contribute to the decreased tumor burden. This is not considered in the interpretation of the in vivo results.
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