RESUMO
Osimertinib is a third-generation inhibitor approved for the treatment of non-small cell lung cancer. It overcomes resistance to first-generation inhibitors by incorporating an acrylamide group which alkylates Cys797 of EGFR T790M. The mutation of a residue in the P-loop (L718Q) was shown to cause resistance to osimertinib, but the molecular mechanism of this process is unknown. Here, we investigated the inhibitory process for EGFR T790M (susceptible to osimertinib) and EGFR T790M/L718Q (resistant to osimertinib), by modelling the chemical step (i.e., alkylation of Cys797) using QM/MM simulations and the recognition step by MD simulations coupled with free-energy calculations. The calculations indicate that L718Q has a negligible impact on both the activation energy for Cys797 alkylation and the free-energy of binding for the formation of the non-covalent complex. The results show that Gln718 affects the conformational space of the EGFR-osimertinib complex, stabilizing a conformation of acrylamide which prevents reaction with Cys797.
RESUMO
A preterm boy died 4 days after delivery from septicaemia which at necropsy was found to be due to perforation of an eosinophilic lesion of the terminal ileum. Eosinophilic infiltration was also found in kidney, lymph node, bone marrow, portal tracts of liver, gall bladder, and bile duct with associated obstruction of the cystic duct and mucocele of the gall bladder. No allergic cause for the infiltrate was found in either the infant or his mother. Eosinophilic infiltration of neonatal spleen, lymph node, intestinal mucosa, epicardium, thymus, pancreas, portal tracts of the liver, and skin has been reported but the aggressive behaviour of the infiltrate in this patient bears more resemblance to the eosinophilic gastroenteritis that has been described in older children and adults.