Impact of compound mutations I1171N + F1174I and I1171N + L1198H on the structure of ALK in NSCLC pathogenesis: atomistic insights.

Anaplastic lymphoma kinase (ALK) fusion genes are found in 3%-5% of non-small cell lung cancers (NSCLCs). NSCLC is the most common type of lung cancer, accounting for 84% of all lung cancer diagnoses. Available treatment options for ALK-positive NSCLCs involve the use of ALK tyrosine kinase inhibitors (ALK-TKIs) which have shown to be effective with a high response rate. Nonetheless, the emergence of multiple compound mutations such as I1171N + F1174I or I1171N + L1198H has been reported to cause resistance to all approved ALK-TKIs. However, the underlying molecular mechanisms surrounding the impact of these compound mutants remain poorly understood. Hence, we performed molecular dynamics simulations to characterize the structural effects and functional implications of these compound mutations. Findings revealed a destabilizing effect on ALK by mutants as compared to the wild-type ALK structure. Also, further insights revealed a lower root-mean-squared fluctuation, radius of gyration, and solvent-accessible surface area values of I1171N + F1174I and I1171N + L1198H ALK compound mutations suggesting that the mutants have a more compact structure and a smaller surface area than the wild-type protein. The mutants also distorted the activation loop residues (Tyr1278, Tyr1282, and Tyr1283) in the ALK structure, which further identify them as possible disruptors of phosphorylation. In contrast to wild conformation, the mutant conformations exhibited a reduced node degree in their residue interaction networks. Collectively, our findings provide deeper insights into the deleterious effects of I1171N + F1174I and I1171N + L1198H ALK compound mutations, which may contribute to NSCLC pathogenesis.Communicated by Ramaswamy H. Sarma.