TKI type switching overcomes ROS1 L2086F in ROS1 fusion-positive cancers Journal Article
| Authors: | Thawani, R.; Repetto, M.; Keddy, C.; Nicholson, K.; Jones, K.; Nusser, K.; Beach, C. Z.; Harada, G.; Drilon, A.; Davare, M. A. |
| Article Title: | TKI type switching overcomes ROS1 L2086F in ROS1 fusion-positive cancers |
| Abstract: | The grammar in this abstract is generally correct, but there’s a minor issue with sentence structure in one part. Here’s a slightly revised version with improved grammar and flow: ROS1 tyrosine kinase inhibitors (TKIs) are highly effective in ROS1-positive non-small cell lung cancer, but resistance remains a challenge. We investigated the activity of various TKIs against wildtype and mutant ROS1, focusing on the emerging L2086F resistance mutation. Using Ba/F3 and NIH3T3 cell models, CRISPR/Cas9-edited isogenic wildtype and mutant patient-derived cell lines, and in vivo tumor growth studies, we compared type I TKIs (crizotinib, entrectinib, taletrectinib, lorlatinib, and repotrectinib) to type II TKIs (cabozantinib and merestinib) and the type I FLT3 inhibitor gilteritinib. The ROS1 L2086F mutant kinase showed resistance to type I TKIs, while type II TKIs retained activity. Gilteritinib inhibited both wildtype and L2086F mutant ROS1 but was ineffective against the G2032R mutation. Structural analyses revealed distinct binding poses for cabozantinib and gilteritinib, explaining their efficacy against L2086F. Clinical cases demonstrated cabozantinib’s effectiveness in patients with TKI-resistant, ROS1 L2086F mutant NSCLCs. This study provides the first comprehensive report of ROS1 L2086F in the context of later-generation TKIs, including macrocyclic inhibitors. While cabozantinib effectively inhibits ROS1 L2086F, its multi-kinase inhibitor nature highlights the need for more selective and better-tolerated TKIs to overcome kinase-intrinsic resistance. Gilteritinib may offer an alternative for targeting ROS1 L2086F with distinct off-target toxicities, but further studies are required to fully evaluate its potential in this setting. © The Author(s) 2024. |
| Keywords: | controlled study; unclassified drug; gene mutation; human cell; drug efficacy; nonhuman; polymerase chain reaction; mouse; cell viability; animal experiment; animal model; in vivo study; protein tyrosine kinase inhibitor; cell culture; western blotting; clonogenic assay; complementary dna; non small cell lung cancer; short tandem repeat; peptides and proteins; crizotinib; cabozantinib; protein ros1; human; article; entrectinib; gilteritinib; crispr-cas9 system; lorlatinib; malignant neoplasm; nih 3t3 cell line; ba/f3 cell line; lung non-small cell carcinoma cell line; repotrectinib; merestinib; taletrectinib; cuto 28 cell line |
| Journal Title: | npj Precision Oncology |
| Volume: | 8 |
| ISSN: | 2397-768X |
| Publisher: | Springer Nature |
| Date Published: | 2024-08-08 |
| Start Page: | 175 |
| Language: | English |
| DOI: | 10.1038/s41698-024-00663-1 |
| PROVIDER: | scopus |
| PMCID: | PMC11310217 |
| PUBMED: | 39117775 |
| DOI/URL: | |
| Notes: | Erratum issued, see: 10.1038/s41698-024-00676-w -- The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Alexander Drilon -- Source: Scopus |
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