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A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
Atomistic insights into the lung cancer-associated L755P mutation in HER2 resistance to lapatinib: a molecular
Bei Yang1, Haiping Zhang, Hao Wang
1Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, Shanghai, 200433, China.
Abstract:
HER2, a member of the human ErbB protein family belonging to receptor tyrosine kinases, plays important roles in regulating crucial cellular processes, including cell migration, proliferation, and differentiation. A missense mutation, L755P, in the HER2 kinase domain has been involved in lung cancer in humans and exhibits reduced response to lapatinib therapy. However, the detailed mechanism of how the HER2 L755P mutation causes drug resistance to lapatinib remains elusive. Here, molecular docking, molecular dynamics (MD) simulations, binding free energy calculations [molecular mechanics and generalized Born/surface area (MM-GBSA)] were performed to reveal the mechanism of drug resistance due to the HER2 L755P mutation. MD simulations revealed that the L755P mutation caused structural changes in the regions of helix αC, the glycine-rich loop, and the activation loop, thereby leading to the loss of interactions between the solubilizing group of lapatinib and HER2. Moreover, MM-GBSA calculations suggested that hydrophobic interactions between lapatinib and HER2 contribute most to the binding affinity, and that the L755P mutation could result in a less energetically favorable HER2/lapatinib complex. This may weaken the binding of lapatinib to the mutated HER2, thereby leading to the emergence of drug resistance. This study offers a structural explanation for the effect of the L755P mutation on the HER2/lapatinib complex.
Insights
The HER2 L755P mutation in lung cancer reduces lapatinib effectiveness by altering protein structure, weakening drug binding. This study reveals the molecular basis for lapatinib resistance in HER2-mutated cancers.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- HER2 (human epidermal growth factor receptor 2) is a key protein in cellular processes and a target in cancer therapy.
- The L755P mutation in HER2 is linked to lung cancer and reduced sensitivity to lapatinib, a targeted therapy.
- The precise mechanism underlying this drug resistance remains unclear.
Purpose of the Study:
- To elucidate the molecular mechanism by which the HER2 L755P mutation confers resistance to lapatinib.
- To provide a structural explanation for the reduced efficacy of lapatinib in HER2-mutated lung cancer.
Main Methods:
- Molecular docking simulations to predict binding interactions.
- Molecular dynamics (MD) simulations to analyze structural changes.
- Molecular mechanics and generalized Born/surface area (MM-GBSA) calculations for binding free energy estimation.
Main Results:
- The L755P mutation induces structural alterations in critical HER2 regions (helix αC, glycine-rich loop, activation loop).
- These structural changes disrupt key interactions between lapatinib and HER2, particularly hydrophobic interactions.
- The mutated HER2/lapatinib complex is less energetically favorable, indicating weakened binding affinity.
Conclusions:
- The HER2 L755P mutation causes drug resistance by destabilizing the HER2/lapatinib complex through structural modifications.
- This study provides a detailed structural insight into lapatinib resistance mediated by the HER2 L755P mutation.
- Findings may inform the development of strategies to overcome resistance in HER2-driven lung cancers.
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