Strategies to Overcome Intrinsic and Acquired Resistance to Chemoradiotherapy in Head and Neck Cancer

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review provides a broad overview of molecular mechanisms related to chemo-radioresistance in head and neck cancer. While the content is comprehensive, it largely focuses on general concepts and lacks updated or specific information. Below are a few suggestions to enhance the quality and depth of the paper:

1.   Cancer Stem Cells Section: The discussion in this section primarily emphasizes the role of the CD44 molecule in cancer stemness. While CD44 is a well-established endpoint marker of stem cells, it does not function as an upstream regulator. I recommend including information on upstream stemness regulators that contribute to radioresistance in head and neck cancer, such as GRP78, to provide a more nuanced and comprehensive understanding of this mechanism.

2.   Non-Coding RNA Section: The field of microRNA (miRNA) research is advancing rapidly, with findings highlighting their tissue-specific roles. However, the authors mainly cite studies involving other cancers, such as hepatocellular carcinoma, renal cell carcinoma, bladder cancer, and ovarian cancer, rather than focusing on head and neck cancer. Recently, several novel miRNAs associated with radioresistance in head and neck cancer have been identified. For example, miR-630 has been shown to promote radioresistance by inducing anti-apoptotic effects via the Nrf2-GPX2 molecular axis in head and neck cancer. I suggest incorporating more recent findings specific to head and neck cancer to ensure the review accurately reflects the latest advancements in this area.

 

3.   References: The references require careful review and revision. Although the article focuses on head and neck cancer, many examples cited pertain to other cancers, especially in the section on non-coding RNA. I recommend revising the references to focus exclusively on studies related to head and neck cancer to better align with the scope of the paper.

 

4. The manuscript has a few noticeable grammar mistakes. For example, in the second paragraph of the Introduction, the authors write, “In this review, we will discuss…” The sentence should use the past tense rather than the future tense. I recommend carefully reviewing the entire text for grammar and consistency.

Comments on the Quality of English Language

The manuscript has a few noticeable grammar mistakes. For example, in the second paragraph of the Introduction, the authors write, “In this review, we will discuss…” The sentence should use the past tense rather than the future tense. I recommend carefully reviewing the entire text for grammar and consistency.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript comprehensively addresses the intrinsic and acquired resistance mechanisms to chemoradiotherapy (CRT) in head and neck cancer (HNC). The authors discuss various factors contributing to resistance, including overexpression of efflux pumps, perturbation of apoptosis-related factors, increased antioxidant expression, glucose metabolism, metallothionein expression, enhanced DNA repair, cancer stem cells, epithelial-mesenchymal transition (EMT), non-coding RNA, and the tumor microenvironment. The paper also summarizes techniques for generating acquired resistance in vitro and recent advances in targeting these resistance mechanisms to sensitize HNC cells to CRT.

The manuscript is comprehensive, covering a wide range of resistance mechanisms and therapeutic targets. It provides a detailed discussion of the tumor microenvironment and its role in therapy resistance. The inclusion of in vitro models for generating acquired resistance is valuable for experimental research.

The manuscript could benefit from a more structured presentation, possibly dividing the content into clearer sections based on resistance mechanisms and therapeutic strategies. While the paper discusses various therapeutic targets, it could provide a more integrated view of how these targets might be combined in clinical practice to overcome resistance. The manuscript lacks a discussion on the clinical implications and potential challenges of implementing these targeted therapies in HNC patients.

Author Response

please see the attachment

Author Response File: Author Response.pdf