Primary Resistance to EGFR Tyrosine Kinase Inhibitors (TKIs): Contexts and Comparisons in EGFR-Mutated Lung Cancer

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The review manuscript titled “Primary Resistance to EGFR Tyrosine Kinase Inhibitors (TKIs) in EGFR-mutated Lung Cancer” systematically overviewed the potential cause of drug resistance in seven-layer pyramid dynamics.

My comments:

1.      Although it is interesting to know the potential causes of primary resistance to EGFR TKIs, many causes are also the potential cause related to acquired resistance to EGFR TKIs. It is hard to differentiate the primary resistance and acquired resistance, especially the late acquired primary resistance and acquired resistance. The title may not be accurate.

2.      There is an unmet need for treating the resistance, either primary resistance or acquire resistance, of EGFR-mutant NSCLC patients to EGFR TKIs. The angle for treating them might be differentiated since the cause is not the same. It will be interesting to further discuss the current treatment strategies using successful stories for these two types of resistance.

 

3.      Other than targeted therapy in EGFR-mutant lung cancer patients, immunotherapy not limited to anti-PD1/PD-L1 treatment, might be beneficial to these group of patients. Further discuss the baseline difference of the primary and acquired EGFR TKI resistant NSCLC patients, might be interesting to know.

Comments on the Quality of English Language

The manuscript was generally well-written. Further polishing and double-checking could make it better.

Author Response

The review manuscript titled “Primary Resistance to EGFR Tyrosine Kinase Inhibitors (TKIs) in EGFR-mutated Lung Cancer” systematically overviewed the potential cause of drug resistance in seven-layer pyramid dynamics.

My comments:

1. Although it is interesting to know the potential causes of primary resistance to EGFR TKIs, many causes are also the potential cause related to acquired resistance to EGFR TKIs. It is hard to differentiate the primary resistance and acquired resistance, especially the late acquired primary resistance and acquired resistance. The title may not be accurate.

Thank you for your insightful comments and constructive feedback on my manuscript. After careful consideration of your suggestions regarding the title of my review article, I have decided to revise it to more accurately reflect the focus and scope of our research.

 The new title I propose is: "Primary Resistance to EGFR Tyrosine Kinase Inhibitors (TKIs): Contexts and Comparisons in EGFR-Mutated Lung Cancer."

2. There is an unmet need for treating the resistance, either primary resistance or acquire resistance, of EGFR-mutant NSCLC patients to EGFR TKIs. The angle for treating them might be differentiated since the cause is not the same. It will be interesting to further discuss the current treatment strategies using successful stories for these two types of resistance.

Thank you for your valuable feedback on my manuscript. While I appreciate the suggestion to explore both primary and acquired resistance in EGFR-mutant NSCLC patients treated with EGFR TKIs, I prefer to maintain the focus on primary resistance. This area, I believe, still presents many unexplored aspects and fills a critical gap in current research.

Expanding the scope to include detailed discussions on acquired resistance might risk overcomplicating the narrative and could divert attention from the targeted exploration of primary resistance, which is the main objective of my review. There is substantial research available on acquired resistance, and my manuscript aims to add a focused and distinct perspective on primary resistance.

 I value your insights and did consider a broader approach. However, I am convinced that a concentrated examination of primary resistance will be more impactful and engaging for our audience.

 Thank you again for your suggestions, and I hope this clarifies the rationale behind my manuscript's focus.

3. Other than targeted therapy in EGFR-mutant lung cancer patients, immunotherapy not limited to anti-PD1/PD-L1 treatment, might be beneficial to these group of patients. Further discuss the baseline difference of the primary and acquired EGFR TKI resistant NSCLC patients, might be interesting to know.

Thank you for your insightful suggestion to discuss immunotherapy options, including beyond anti-PD1/PD-L1 treatments, for EGFR-mutant lung cancer patients. Your emphasis on exploring the baseline differences in primary and acquired EGFR TKI resistant NSCLC patients is well-taken.

 In response, I have added a new subsection titled "5.1 Immunity" under the TME section of my manuscript. This addition specifically addresses your concerns, highlighting how drug exposure impacts tumor and tumor-infiltrating immune cells. As stated in the new section:

 "5.1 Immunity: Drug exposure affects tumor and tumor-infiltrating immune cells. Programmed death-ligand 1 (PD-L1) expression in EGFR-mutant NSCLC cells can be downregulated by EGFR TKIs, leading to the lack of efficacy of PD-1/PD-L1 inhibitors in most EGFR-mutant NSCLC patients. Similarly, EGFR-mutant NSCLC cell lines with higher PD-L1 expression are resistant to gefitinib, as PD-L1 overexpression may stimulate epithelial-mesenchymal transition (EMT) by activating the TGF-β/Smad canonical signaling pathway. AXL, a member of the receptor tyrosine kinase family, has been associated with innate resistance to programmed cell death protein-1 (PD-1) inhibition and suppression of proper antigen presentation by major histocompatibility complex (MHC)-I, suggesting that inhibiting AXL could mediate favorable reprogramming of the immune-suppressive TME."

 I hope this addition will provide a comprehensive perspective on the immunological aspects in EGFR-mutant NSCLC, addressing your suggestion to expand my discussion in this area.

 Thank you again for your constructive feedback, which has been instrumental in enhancing the depth and scope of my manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

This is very interesting  review about the efficacy of tyrosine kinase inhibitors (TKIs) in epidermal growth fac-tor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients. 

 I liked the idea that "intrinsic primary resistance" is characterized by pre-existing somatic and genomic changes, and cell of origins, while "late primary resistance" is correlated with the drug-tolerant persister state.

Comments on the Quality of English Language

Author must check English

Author Response

This is very interesting review about the efficacy of tyrosine kinase inhibitors (TKIs) in epidermal growth fac-tor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients.

 I liked the idea that "intrinsic primary resistance" is characterized by pre-existing somatic and genomic changes, and cell of origins, while "late primary resistance" is correlated with the drug-tolerant persister state.

Thank you for your positive feedback on my review of TKIs in EGFR-mutated NSCLC. I am glad you found the distinction between "intrinsic primary resistance" and "late primary resistance" insightful. Your support and recognition are greatly appreciated.