Targeting arachidonic acid-modulated autophagy: a novel axis in crizotinib resistance

I read with interest the article by Jie et al., “Targeting of arachidonic acid-modulated autophagy to enhance the sensitivity of ROS1+ or ALK+ non-small cell lung cancer to crizotinib therapy”, published in Translational Lung Cancer Research (1). This study introduces a promising mechanistic insight into crizotinib resistance in non-small cell lung cancer (NSCLC), a persistent clinical hurdle (2).

The authors report that in crizotinib-resistant NSCLC cells with anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 (ROS1) rearrangements, a decline in p-STAT3 and PTGS2 expression results in the intracellular buildup of arachidonic acid (AA). This buildup, in turn, appears to stimulate autophagy, potentially supporting resistance to crizotinib. Notably, they found that the autophagy inhibitor chloroquine (CQ) could counteract this effect, restoring sensitivity to the drug (1). Identifying this AA-driven autophagy pathway provides valuable direction in understanding resistance mechanisms tied to altered metabolism (3).

While the therapeutic potential of CQ repurposing is intriguing, several limitations warrant discussion. The study’s conclusions rely on two cell lines, emphasizing the need for validation using diverse models, including animal studies and clinical samples (1). Additionally, although the mechanism downstream of STAT3/PTGS2 was explored, upstream regulatory factors were not addressed. The safety profile of CQ, especially for prolonged clinical use, should also be carefully evaluated.

Studies have shown increasing investigations of autophagy in drug resistance and possible therapeutic use of inhibitors of autophagy as chemo-sensitizers, which agree with precedent findings in other malignancies (4). In vivo preclinical proof-of-concept for crizotinib-CQ combination studies and well-designed clinical trials with biomarker analysis in patients with crizotinib-resistant ROS1/ALK-NSCLC should constitute priority future research directions. Investigation of upstream regulators of p-STAT3/PTGS2 and other possible alternative autophagy inhibitors dealing with enhanced safety profile will remain very important steps (5).

In summary, Jie et al. have identified an important mechanism linking AA metabolism and autophagy to resistance against crizotinib (1). While additional work still lies ahead, their findings provide a strong rationale for pursuing the therapeutic potential of targeting this pathway to overcome resistance in ALK/ROS1-rearranged NSCLC.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-524/coif). The author has no conflicts of interest to declare.

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References

1. Jie H, Lai H, Wang Z, et al. Targeting of arachidonic acid-modulated autophagy to enhance the sensitivity of ROS1 (+) or ALK (+) non-small cell lung cancer to crizotinib therapy. Transl Lung Cancer Res 2025;14:878-96. [Crossref] [PubMed]
2. Ouverney G, Hottz D, Robbs BK. Drug Resistance and Novel Targets for Cancer Therapy: An Overview of Recent Findings. Biomedicines 2024;12:816. [Crossref] [PubMed]
3. Tang FH, Wong HYT, Tsang PSW, et al. Recent advancements in lung cancer research: a narrative review. Transl Lung Cancer Res 2025;14:975-90. [Crossref] [PubMed]
4. Singh MP, Cho HJ, Kim JT, et al. Morin Hydrate Reverses Cisplatin Resistance by Impairing PARP1/HMGB1-Dependent Autophagy in Hepatocellular Carcinoma. Cancers (Basel) 2019;11:986. [Crossref] [PubMed]
5. Janku F, Garrido-Laguna I, Petruzelka LB, et al. Novel therapeutic targets in non-small cell lung cancer. J Thorac Oncol 2011;6:1601-12. [Crossref] [PubMed]