Anaplastic lymphoma kinase (ALK) G1202R (ALK G1202R)

Anaplastic lymphoma kinase (ALK) G1202R is a specific resistance mutation located in the solvent front of the ALK tyrosine kinase domain (OncoKB, NIH). This mutation typically emerges in patients with ALK-rearranged non-small cell lung cancer (NSCLC) following treatment with first-generation (crizotinib) or second-generation (alectinib, ceritinib, brigatinib) ALK tyrosine kinase inhibitors (TKIs) (ascopubs.org, NIH). The substitution of glycine with a bulky arginine residue at position 1202 creates steric hindrance that prevents most earlier-generation inhibitors from binding effectively to the ATP-binding pocket (NIH). Biologically, the G1202R mutation maintains the constitutive signaling of ALK fusion proteins, driving oncogenic pathways such as PI3K/AKT and MAPK/ERK that promote cell proliferation, survival, and epithelial-mesenchymal transition (EMT) (NIH). Third-generation TKIs like lorlatinib were specifically engineered with a macrocyclic structure to overcome this steric hindrance and remain potent against the G1202R variant (ascopubs.org, NIH). However, the continued evolution of the kinase domain can lead to compound mutations, such as G1202R combined with L1196M, which pose significant therapeutic challenges and necessitate the development of next-generation inhibitors like NVL-655 and repotrectinib (Genomenon, ResearchGate).

Other names

ALK G1202R mutationALK solvent front mutationEML4-ALK G1202Rp.Gly1202Arg

Tyrosine kinase inhibition