Exploiting Synthetic Lethality of PRMT5 for Precision Treatment of MTAP-Deficient Glioblastoma

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The study is a review discussing a role of arginine methyltransferase 5 (PRMT5) and consequences a synthetic lethality targeting PRMT5 in methylthioadenosine phosphorylase (MTAP)-deleted GBM. This well known example, when loss of MTAP leads to the accumulation of methylthioadenosine (MTA), a metabolite that partially inhibits PRMT5, create a selective vulnerability to PRMT5 inhibitors. The authors critically assess preclinical and clinical data on both first- and second-generation PRMT5 inhibitors, with particular emphasis on MTA-cooperative compounds. The review is well written , concise yet comprehensive, very focused on a specific aspect. The assessment of PRMT5 inhibitors is competent and informative.

Minor comments:

• Please use italics when PRMT5 gene expression is discussed.
• Some sentences about PRMT5 are too general, i.e. cytoplasmic PRMT5 has been implicated in the regulation of splicing and translation processes. It would be nice to present more details how it act in those processes, particularly if most functions are nuclear. How assemble of Chloride Channel Nucleotide-Sensitive 1A (pICln) with PRMT5 fits to known functions?
• Please comment if adverse events of PRMT5 inhibitors were common in different preclinical studies or unique to some inhibitors. Table 1 is missing the information about adverse effects in some trials. Details regarding specific trials are not equal, sometimes there is much more information including patient numbers. More uniform information would be desired.
• Some of the discussed inhibitors i.e. JNJ-64619178 were tested in non-CNS tumors. What are chances that the compound would pass BBB?

 

Author Response

We sincerely thank the reviewers for their thoughtful and constructive comments on our manuscript. Their valuable feedback helped us clarify key points and strengthen the overall quality of the work. We have carefully addressed all suggestions and made the corresponding revisions throughout the manuscript. We appreciate the time and effort the reviewers dedicated to improving our study.

 

Reviewer 1:

The study is a review discussing the role of arginine methyltransferase 5 (PRMT5) and consequences of synthetic lethality targeting PRMT5 in methylthioadenosine phosphorylase (MTAP)-deleted GBM. This well-known example, when loss of MTAP leads to the accumulation of methylthioadenosine (MTA), a metabolite that partially inhibits PRMT5, creates a selective vulnerability to PRMT5 inhibitors. The authors critically assess preclinical and clinical data on both first- and second-generation PRMT5 inhibitors, with particular emphasis on MTA-cooperative compounds. The review is well written, concise yet comprehensive, very focused on a specific aspect. The assessment of PRMT5 inhibitors is competent and informative.

Minor comments:

• Please use italics when PRMT5 gene expression is discussed.

Response: We have ensured that PRMT5 gene expression is italicized throughout the manuscript, as highlighted in red.

 

• Some sentences about PRMT5 are too general, i.e. cytoplasmic PRMT5 has been implicated in the regulation of splicing and translation processes. It would be nice to present more details how it act in those processes, particularly if most functions are nuclear. How assemble of Chloride Channel Nucleotide-Sensitive 1A (pICln) with PRMT5 fits to known functions?

Response: Thank you for the helpful comment. We agree that the description of cytoplasmic PRMT5 functions could be more specific. To address this, we have added additional mechanistic details to clarify how cytoplasmic PRMT5 contributes to both splicing and translation (Manuscript, lines 121–129).

 

Regarding pICln, we have expanded the text to clarify its role as a key adaptor within the cytoplasmic PRMT5 complex, where it recruits Sm proteins for symmetric arginine methylation (Manuscript, lines 111–129).

 

• Please comment if adverse events of PRMT5 inhibitors were common in different preclinical studies or unique to some inhibitors. Table 1 is missing the information about adverse effects in some trials. Details regarding specific trials are not equal, sometimes there is much more information including patient numbers. More uniform information would be desired.

Response: Adverse events associated with PRMT5 inhibitors have been consistently reported in multiple preclinical studies, suggesting that certain side effects may be intrinsic to this class of drugs due to their common mechanism of action. Frequently observed adverse events include fatigue, anemia, nausea, thrombocytopenia, and neutropenia.

 

We have updated Table 1 to provide a more standardized and coherent presentation of information across the listed clinical trial. Please note that several ongoing trials remain in the recruitment phase and thus lack available results, published data, or reported conclusions. This status has been clearly indicated in the table to distinguish completed studies from those still active (Manuscript, page 5).

 

• Some of the discussed inhibitors i.e. JNJ-64619178 were tested in non-CNS tumors. What are chances that the compound would pass BBB?

Response: JNJ-64619178 has shown activity in non-CNS tumors, but its ability to cross the BBB is still unclear (PMID: 37491846, PMID: 34583982). While it is a small molecule with properties that might support BBB penetration, other critical factors like lipophilicity and efflux by transporters also play a role. Currently, no data confirms its distribution in the brain, and its development has focused on peripheral cancers.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript presents a comprehensive analysis of the potential of targeting PRMT5 in MTAP-deficient glioblastoma through synthetic lethality. However, I have a few suggestions as outlined below.

1. The first-generation PRMT5-targeting drugs exhibited clear limitations, particularly regarding selectivity. As a result, their clinical utility remains limited. Therefore, I recommend minimizing the detailed discussion of each first-generation compound in the main text. Instead, the review would benefit from a stronger focus on second-generation PRMT5-targeting modalities, including recent advancements such as PROTAC-based degraders and antisense oligonucleotide (ASO) approaches. These newer strategies provide more precise targeting and may offer improved therapeutic windows, making them particularly relevant for translational applications. Additionally, it would be helpful to expand the discussion beyond glioblastoma (GBM). Emerging evidence suggests that PRMT5-targeted therapies could be applicable to other tumor types—highlighting this broader potential would significantly enhance the relevance and impact of the review
2. The section discussing the combination of PRMT5 inhibition with PD-1 immune checkpoint blockade would benefit from further elaboration. Currently, the mechanistic rationale for this combination is not sufficiently explained. Please consider providing a more detailed discussion on how PRMT5 inhibition may influence the tumor immune microenvironment that could sensitize tumors to PD-1 inhibition. Several recent studies have indicated that PRMT5 plays a role in immune evasion, T cell infiltration, and regulation of immune-related gene expression. Including this mechanistic context would strengthen the justification for this combination strategy and help readers understand its translational relevance.
3. Minor comments.

   • Line 23: “residue function” → should read “residual function”.

   • Line 215+: Please clarify the clinical status of LLY-283 (preclinical or in trials?).

Author Response

We sincerely thank the reviewers for their thoughtful and constructive comments on our manuscript. Their valuable feedback helped us clarify key points and strengthen the overall quality of the work. We have carefully addressed all suggestions and made the corresponding revisions throughout the manuscript. We appreciate the time and effort the reviewers dedicated to improving our study.

Reviewer 2:

This manuscript presents a comprehensive analysis of the potential of targeting PRMT5 in MTAP-deficient glioblastoma through synthetic lethality. However, I have a few suggestions as outlined below.

1. The first-generation PRMT5-targeting drugs exhibited clear limitations, particularly regarding selectivity. As a result, their clinical utility remains limited. Therefore, I recommend minimizing the detailed discussion of each first-generation compound in the main text. Instead, the review would benefit from a stronger focus on second-generation PRMT5-targeting modalities, including recent advancements such as PROTAC-based degraders and antisense oligonucleotide (ASO) approaches. These newer strategies provide more precise targeting and may offer improved therapeutic windows, making them particularly relevant for translational applications. Additionally, it would be helpful to expand the discussion beyond glioblastoma (GBM). Emerging evidence suggests that PRMT5-targeted therapies could be applicable to other tumor types—highlighting this broader potential would significantly enhance the relevance and impact of the review.

Response: Thank you for your insightful feedback. We agree that the clinical limitations of first-generation PRMT5 inhibitors, particularly their lack of selectivity, have limited their translational potential. Although second-generation PRMT5 inhibitors exhibit improved selectivity, their efficacy is limited to MTAP-deficient tumors, which represent only 10–15% of all human cancers, as they specifically target PRMT5 in complex with the abundance of MTA. As a result, first-generation PRMT5 inhibitors continue to be evaluated in clinical trials, with ongoing efforts to improve their specificity and reduce toxicity to normal cells.

 

We also acknowledge the promise of emerging strategies such as PROTAC-based degraders, which offer enhanced selectivity and potentially broader therapeutic windows (PMID: 39614393 and PMID: 40232306). However, to date, these agents have been tested in clinical trials for GBM.

 

In response to your comments, we have expanded the manuscript to highlight the broader translational potential of these novel modalities across other cancer types, including mesothelioma, pancreatic adenocarcinoma, non-small cell lung cancer (NSCLC), and cholangiocarcinoma (Manuscript, lines 498-502).

 

1. The section discussing the combination of PRMT5 inhibition with PD-1 immune checkpoint blockade would benefit from further elaboration. Currently, the mechanistic rationale for this combination is not sufficiently explained. Please consider providing a more detailed discussion on how PRMT5 inhibition may influence the tumor immune microenvironment that could sensitize tumors to PD-1 inhibition. Several recent studies have indicated that PRMT5 plays a role in immune evasion, T cell infiltration, and regulation of immune-related gene expression. Including this mechanistic context would strengthen the justification for this combination strategy and help readers understand its translational relevance.

Response: We have included more detailed texts of the underlying mechanisms by which PRMT5 inhibition modulates the tumor immune microenvironment, including its effects on T cell infiltration and immune checkpoint regulation. These changes may contribute to an enhanced antitumor immune response and provide a rationale for combining PRMT5 inhibitors with PD-1 blockade to potentially improve therapeutic efficacy (Manuscript, lines 459-463).

 

1. Minor comments.
• Line 23: “residue function” → should read “residual function”.

Response: We changed it to “residual function”. (Manuscript, line 23)

• Line 215+: Please clarify the clinical status of LLY-283 (preclinical or in trials?).

Response: We have highlighted that LLY-283 is still being evaluated for GBM in preclinical studies (Manuscript, line 229).

 

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The author has appropriately incorporated the suggestions and comments we previously provided. The revised manuscript reflects a clear effort to address the raised concerns in a thoughtful and constructive manner, thereby improving the overall clarity, scientific rigor, and coherence of the work. We appreciate the author’s responsiveness and willingness to engage with the feedback in a meaningful way.