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Computer simulations help understand lung cancer drug resistance

Scientists from the Universities of Bristol and Parma, Italy, have used computer simulations to understand drug resistance to osimertinib. Findings of this study are published in journal Chemical Science.

Osimertinib works by binding to epidermal growth factor receptor (EGFR), which is over expressed in many tumors. EGFR is involved in a pathway that signals for cell proliferation, and so is a target for drugs. Blocking the action of EGFR (inhibiting it) can switch it off, and so is a good way to treat tumors. Osimertinib is used to treat non-small-cell lung cancer (NSCLC), in cases where the cancer cells have a particular (T790M) mutant form of EGFR.

Osimertinib drug resistance computer simulations
Credit: University of Bristol

Although patients generally respond well to osimertinib, most acquire drug resistance within one year of treatment, so the drug stops working. Drug resistance arises because the EGFR protein mutates, so that the drug binds less tightly. One such mutation, called L718Q, was recently discovered in patients in the clinic by the Medical Oncology Unit of the University Hospital of Parma. In this drug resistant mutant, a single amino acid is changed. Unlike other drug resistant mutants, it was not at all clear how this change stops the drug from binding effectively, information potentially crucial in developing new drugs to overcome resistance.

Using a range of advanced molecular simulation techniques which included modelling chemical step using combined quantum mechanics/molecular mechanics and recognition step using molecular dynamics simulations and free energy calculations.  These calculation gave researchers understanding of molecular basis for the drug resistance. Such knowledge could be exploited in future to find solution to problem.

Citation: Callegari, D., K. E. Ranaghan, C. J. Woods, R. Minari, M. Tiseo, M. Mor, A. J. Mulholland, and A. Lodola. “L718Q mutant EGFR escapes covalent inhibition by stabilizing a non-reactive conformation of the lung cancer drug osimertinib.” Chemical Science, 2018. doi:10.1039/c7sc04761d.

Adapted from press release by University of Bristol.

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