Sensitivity of Pancreatic Cancer Cell Lines to Clinically Approved FAK Inhibitors: Enhanced Cytotoxicity Through Combination with Oncolytic Coxsackievirus B3

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Improved therapeutic approaches for pancreatic ductal adenocarcinoma (PDAC), including therapies used in combination, are urgently needed, given the very poor prognosis associated with this disease. In this paper, the authors test combinations of clinically approved FAK inhibitors with an oncolytic virus developed in their group known as PD-H, within a range of pancreatic cancer cell lines. Cell growth inhibition following treatment of FAKi plus PD-H was assessed and combination indices (indicating synergy, additive or antagonistic effects) were calculated in a robust manner. The influence of FAKi on replication and cytotoxicity of PD-H was also studied.

Overall, the work has novelty and will be of interest to researchers working in pancreatic cancer therapy. The work is carried out and written up to a high scientific standard.

Author Response

Thank you very much for the positive assessment of our manuscript. Since no objections or comments were raised, there is nothing further to address. Thank you once again for taking the time to review our work.

Reviewer 2 Report

Comments and Suggestions for Authors

The paper describes the investigation of six FAKi (Defactinib, CEP-37440, VS-4718, VS-6062, Ifebemtinib and GSK2256098) used in clinical trials on five pancreatic tumor cell lines together with the enhancement of their antitumor activity by combination with the oncolytic coxsackievirus B3 (CVB3) strain 20 PD-H. IC50 analyses identified Defactinib and CEP-37440 as the most potent inhibitors of tumor cell 21 growth. VS-4718, VS-6062, and Ifebemtinib showed slightly lower activity, while GSK2256098 was 22 largely ineffective. The combination of Defactinib, CEP-37440, VS-4718, and VS-6062 with PD-H re-23 sulted in varying effects on cytotoxicity, depending on the cell line and the specific FAKi, ranging from no enhancement to a pronounced increase. The synergistic, additive, but also antagonistic interactions between the respective FAKi and PD-H were also assessed. The authors designed a thorough study and clearly presented the methods involved in the experimental assessments. Results were presented in detail and are supported by adequate figures and tables. The authors formulated pertinent conclusions based on the experimental results, The article is written in a fluent style yet using academic terms and can be easily readable.

In my opinion, the paper should be checked in terms of English spelling and phrasing and after that is suited for publication.

Author Response

Thank you very much for your positive evaluation of our manuscript. As there were no major concerns or suggestions, we only made some improvements to the English language throughout the manuscript to improve clarity and readability; these changes are highlighted. We greatly appreciate your time and effort in reviewing our work.