ArticleThoracic cancer2023
Intrinsic resistance to ROS1 inhibition in a patient with CD74-ROS1 mediated by AXL overexpression.
Article in Thoracic cancer, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed, 2 citations in OpenAlex.
- Visceral crisis in a patient with non-small cell lung cancer andTranslational lung cancer research · 2025Article
- Therapeutic advances of targeting receptor tyrosine kinases in cancer.Signal transduction and targeted therapy · 2024Review
- Intrinsic resistance to ROS1 inhibition in a patient with CD74-ROS1 mediated by AXL overexpression.Thoracic cancer · 2023Article
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Authors and funding
6 authors at 3 institutions in 1 country.
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Abstract
backgroundThe vast majority of patients with ROS1 positive non-small cell lung cancer (NSCLC) derive clinical benefit from currently approved ROS1 therapies, including crizotinib and entrectinib. However, a small proportion of patients treated with ROS1 inhibitors fail to derive any clinical benefit and demonstrate rapid disease progression. The biological mechanisms underpinning intrinsic resistance remain poorly understood for oncogene-driven cancers.
methodsWe generated a patient-derived cell line, CUTO33, from a ROS1 therapy naive patient with CD74-ROS1+ NSCLC, who ultimately did not respond to a ROS1 inhibitor. We evaluated a panel of ROS1+ patient-derived NSCLC cell lines and used cell-based assays to determine the mechanism of intrinsic resistance to ROS1 therapy.
resultsThe CUTO33 cell line expressed the CD74-ROS1 gene fusion at the RNA and protein level. The ROS1 fusion protein was phosphorylated at baseline consistent with the known intrinsic activity of this oncogene. ROS1 phosphorylation could be inhibited using a wide array of ROS1 inhibitors, however these inhibitors did not block cell proliferation, confirming intrinsic resistance in this model and consistent with the patient's lack of response to a ROS1 inhibitor. CUTO33 expressed high levels of AXL, which has been associated with drug resistance. Combination of an AXL inhibitor or AXL knockdown with a ROS1 inhibitor partially reversed resistance.
conclusionsIn summary, we demonstrate that AXL overexpression is a mechanism of intrinsic resistance to ROS1 inhibitors.
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