The Druggable Target Potential of NF-κB-Inducing Kinase (NIK) in Cancer

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript describes the NF-kB signaling and its role in tumorogenesis especially by NIK signaling and activation of NF-kB by both canonical and non-canonical pathways. The manuscript is written very well. On of the crictical aspects is that many of the sentences end up in numbers. In addition, the authors are required to modifications as suggested below.

It is advised that authors describe clearly: Line 27-28. “discovered by the Baltimore Laboratory in 1986”

I see that many of the sentences are ending with a number at the end. It would read better and look better if the sentences do not end with a number. I site two such sentences below. There are more such sentences. Some of the sentences ending in number are absurd.

Line 185-188: Fix the sentence “Yulia et 185 al. reported that two NIK inhibitors, described in patent WO2009158011 A1, demonstrated 186 selective toxicity in multiple myeloma cell lines, with a 1 to 5 μM range, specifically tar- 187 geting cells with mutations linked to NF-κB activation 48.” By NOT ending the number “48” at the end of sentence.

Line 194-196: This line is again ending with a number “Moreover, the survival of PTCL cell lines was 194 shown to depend on the activation of both canonical and non-canonical NF-κB pathways, 195 with NIK playing a crucial regulatory role in both 51.”

Correct the sentence: Line 245-258 “NIK has  been found is linked to NF-κB activation in basal-like breast cancer. B-cell lymphoma 3  (Bcl3), which can form a DNA-binding complex with p52, has also been observed to be overexpressed in breast cancer samples61.”

Comments on the Quality of English Language

English language is fine except that many sentences are ending in a number.

Author Response

The manuscript describes the NF-kB signaling and its role in tumorogenesis especially by NIK signaling and activation of NF-kB by both canonical and non-canonical pathways. The manuscript is written very well. On of the crictical aspects is that many of the sentences end up in numbers. In addition, the authors are required to modifications as suggested below.

Response: Thank you very much for taking time to review our manuscript. Please see our responses in detail below:

Comments 1:  It is advised that authors describe clearly: Line 27-28. “discovered by the Baltimore Laboratory in 1986”

Response 1:  Thank you for pointing this out. We agree with this comment. Therefore, we have revised this sentence to “Initially discovered by Sen et al. in 1986…” , please see line 27-28 in the revised manuscript.

Comments 2: I see that many of the sentences are ending with a number at the end. It would read better and look better if the sentences do not end with a number. I site two such sentences below. There are more such sentences. Some of the sentences ending in number are absurd.

Line 185-188: Fix the sentence “Yulia et 185 al. reported that two NIK inhibitors, described in patent WO2009158011 A1, demonstrated 186 selective toxicity in multiple myeloma cell lines, with a 1 to 5 μM range, specifically tar- 187 geting cells with mutations linked to NF-κB activation 48.” By NOT ending the number “48” at the end of sentence.

Line 194-196: This line is again ending with a number “Moreover, the survival of PTCL cell lines was 194 shown to depend on the activation of both canonical and non-canonical NF-κB pathways, 195 with NIK playing a crucial regulatory role in both 51.”

Response 2:  Thank you very much for pointing out these editing errors. In fact, these numbers are reference numbers. We have changed the format of all references numbers to meet the journal’s standard.

Comments 3:  Correct the sentence: Line 245-258 “NIK has  been found is linked to NF-κB activation in basal-like breast cancer. B-cell lymphoma 3  (Bcl3), which can form a DNA-binding complex with p52, has also been observed to be overexpressed in breast cancer samples61.”

Response 3:  Agree. We have revised this sentence. Please see line 245-258 in the revised manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

In the present work Wang et al. reviewed the literature for the potential use of NF-kappaB-inducing Kinase (NIK) as a drug target in cancer. Their work is very interesting and I have enjoyed reading it. Their idea is very interesting and I agree with the authors that NIK (or even other parts of the NF-kappaB circuitry) could have the potential to be used as drug targets to fight cancer. I have only one minor comment, which I would like the authors to address; they have not mentioned at all the case of childhood leukemia and in particular those that are Glucocorticoid (GC) resistant. GC resistance in childhood leukemia is crucial, due to the fact that these are with the worst prognosis. What is known with this type of neoplasms? GC-resistance is probably highly dependent on the NF-kappaB circuits.

Overall, this is a well-written and well-organized manuscript and it has merit for publication.

Author Response

Comments 1:  In the present work Wang et al. reviewed the literature for the potential use of NF-kappaB-inducing Kinase (NIK) as a drug target in cancer. Their work is very interesting and I have enjoyed reading it. Their idea is very interesting and I agree with the authors that NIK (or even other parts of the NF-kappaB circuitry) could have the potential to be used as drug targets to fight cancer. I have only one minor comment, which I would like the authors to address; they have not mentioned at all the case of childhood leukemia and in particular those that are Glucocorticoid (GC) resistant. GC resistance in childhood leukemia is crucial, due to the fact that these are with the worst prognosis. What is known with this type of neoplasms? GC-resistance is probably highly dependent on the NF-kappaB circuits.

Overall, this is a well-written and well-organized manuscript and it has merit for publication.

Response 1: Thank you very much for taking time to review our manuscript. We agree with your comments and have added discussion regarding your point of view, please see below and line 207-213.

Meanwhile, rising incidence of childhood leukemia is associated with activation of the NF-NF-κB pathway. Childhood acute lymphoblastic leukemia (cALL) is the most common pediatric cancer and remains the leading cause of disease-related mortality in children. Glucocorticoid (GC) resistance in cALL is particularly critical, as it is associated with the poorest prognosis. Specific modulation of the expression of key components in the NRAS/BRAF/NF-κB cascade and cell cycle pathways has been shown to effectively restore normal GC responses in GC-resistant pre-B cALL cell lines.