Proto-oncogene tyrosine-protein kinase ROS L2086F mutant (ROS1 L2086F)

The ROS1 L2086F mutant is a clinically significant variant of the proto-oncogene tyrosine-protein kinase ROS (ROS1) that frequently emerges as an acquired resistance mechanism in non-small cell lung cancer (NSCLC) patients harboring ROS1 rearrangements (NIH, 2024; OncoKB, 2026). This specific mutation involves a leucine-to-phenylalanine substitution at residue 2086, which is located in the central β-sheet 6 (Cβ6) of the kinase domain (NIH, 2023). The L2086F mutation is particularly challenging because it confers broad resistance to nearly all type I ROS1 tyrosine kinase inhibitors (TKIs), including crizotinib, entrectinib, lorlatinib, and even newer agents like repotrectinib and taletrectinib (NIH, 2024; AACR, 2021). The resistance is primarily driven by steric hindrance within the ATP-binding pocket, which prevents these inhibitors from binding effectively (NIH, 2024). Despite this resistance, the L2086F mutant remains sensitive to type II TKIs such as cabozantinib and the type I FLT3 inhibitor gilteritinib, which employ distinct binding orientations (NIH, 2024; OncoKB, 2026). Consequently, detecting the L2086F mutation through next-generation sequencing is vital for selecting effective salvage therapies in the setting of TKI resistance (NIH, 2024). This mutation represents an emerging clinical challenge as next-generation TKIs become more widely used in the first-line setting (NIH, 2024). Research continues to focus on developing more selective and better-tolerated inhibitors to overcome this kinase-intrinsic resistance (NIH, 2024).

Other names

ROS1 Leu2086PheROS1 L2086FROS1 Cβ6 mutationROS1 L2086F resistance mutation

Tyrosine kinase inhibition, specifically targeting the ATP-binding pocket of the ROS1 kinase domain to block downstream oncogenic signaling.