Arachidonic acid-mediated autophagy regulation drives crizotinib resistance in lung cancer: therapeutic opportunities and challenges

We sincerely thank Shameer Tahir for the interest in our research and for the thoughtful comments. In this study, by integrating multi-omics data (transcriptomics, metabolomics, single-cell) across two cellular models, we uncovered a novel mechanism of crizotinib resistance in ROS1⁺ or ALK⁺ non-small cell lung cancer (NSCLC), in which arachidonic acid (AA) promotes autophagy flux to reduce drug-induced autophagosome accumulation. Targeting this AA-mediated autophagy with chloroquine (CQ) effectively restored crizotinib sensitivity, suggesting a potential therapeutic strategy for overcoming resistance.

However, this study has certain limitations, as discussed in the manuscript (1). As stated in the comment, the further validation of this mechanism in animal models will be an important next step to strengthen the clinical relevance of our conclusions. On the other hand, the primary objective of our study was to elucidate the role of the STAT3/PTGS2-AA-autophagy flux axis in mediating tyrosine kinase inhibitor (TKI) resistance. While we agree that identifying upstream regulators of STAT3/PTGS2 would be valuable, we consider this to be a distinct and independent research direction that merits future investigation.

Regarding the safety profile of CQ, we acknowledge the concern. CQ has been widely used in the treatment of both acute and chronic inflammatory conditions, such as malaria and rheumatoid arthritis, with an established safety profile in these contexts (2,3). In recent years, CQ has also gained attention as an adjuvant in cancer therapies targeting autophagy. Nevertheless, the precise relationship between its anticancer effects, clinical efficacy, and long-term safety remains to be fully defined. Thus, we concur that the safety of prolonged CQ administration in oncological settings warrants careful evaluation through future preclinical and clinical studies.

We fully agree with the comment regarding the increasing interest in targeting autophagy as a strategy to overcome drug resistance, which is consistent with observations in various other malignancies. The therapeutic potential of autophagy inhibitors, including their role as chemo-sensitizers, represents an exciting area of ongoing research. We also acknowledge that in vivo proof-of-concept studies for the crizotinib-CQ combination, along with well-designed clinical trials incorporating biomarker-based patient stratification, are essential next steps toward clinical translation. Furthermore, the identification of upstream regulators of the p-STAT3/PTGS2 axis, as well as the development or repurposing of alternative autophagy inhibitors with improved safety profiles, will be critical for optimizing future therapeutic strategies.

We appreciate these valuable suggestions, which align with our own perspectives on the direction of future work in this field. Thank you again for the feedback on our manuscript; we appreciate the opportunity to respond.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Editorial Office, Translational Lung Cancer Research. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-615/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

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