Proto-oncogene tyrosine-protein kinase ROS (ROS1) G2032R (ROS1 G2032R)

Proto-oncogene tyrosine-protein kinase ROS (ROS1) G2032R is a specific acquired resistance mutation located in the solvent front of the ROS1 kinase domain. This mutation involves the substitution of glycine at position 2032 with a bulky arginine residue, which sterically hinders the binding of first-generation tyrosine kinase inhibitors (TKIs) like crizotinib (Nature Communications, 2013). It is the most frequent resistance mechanism observed in patients with ROS1-rearranged non-small cell lung cancer (NSCLC) after initial TKI therapy (Journal of Thoracic Oncology, 2020). The G2032R mutation maintains the constitutive activation of downstream signaling pathways, such as PI3K/AKT and MAPK/ERK, which promote tumor cell survival and proliferation. Consequently, this mutant protein has become a critical target for next-generation macrocyclic TKIs, including repotrectinib and taletrectinib, which are designed to bind effectively despite the presence of the bulky arginine side chain (Journal of Clinical Oncology, 2023). Clinical management of ROS1-positive NSCLC increasingly relies on identifying this mutation to guide the transition to these more potent, mutation-specific inhibitors (Cancer Discovery, 2023).

Other names

ROS1 p.Gly2032ArgROS1 solvent front mutationc-Ros receptor tyrosine kinase G2032RROS1 p.G2032R

ATP-competitive inhibition of the ROS1 kinase domain, specifically designed to overcome steric hindrance at the solvent front.