Structural investigations on mechanism of lapatinib resistance caused by HER-2 mutants

Sharad Verma; Sukriti Goyal; Anchala Kumari; Aditi Singh; Salma Jamal; Abhinav Grover

doi:10.1371/journal.pone.0190942

Structural investigations on mechanism of lapatinib resistance caused by HER-2 mutants

PLoS One. 2018 Feb 1;13(2):e0190942. doi: 10.1371/journal.pone.0190942. eCollection 2018.

Authors

Sharad Verma¹, Sukriti Goyal², Anchala Kumari^{1

3}, Aditi Singh^{1

3}, Salma Jamal², Abhinav Grover¹

Affiliations

¹ School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.
² Department of Bioscience and Biotechnology, Banasthali University, Tonk, Rajasthan, India.
³ Department of Biotechnology, TERI School of Advanced Studies, Vasant Kunj, New Delhi, India.

Abstract

HER-2 belongs to the human epidermal growth factor receptor (HER) family. Via different signal transduction pathways, HER-2 regulates normal cell proliferation, survival, and differentiation. Recently, it was reported that MCF10A, BT474, and MDA-MB-231 cells bearing the HER2 K753E mutation were resistant to lapatinib. Present study revealed that HER-2 mutant K753E showed some contrasting behaviour as compared to wild, L768S and V773L HER-2 in complex with lapatinib while similar to previously known lapatinib resistant L755S HER-2 mutant. Lapatinib showed stable but reverse orientation in binding site of K753E and the highest binding energy among studied HER2-lapatinib complexes but slightly lesser than L755S mutant. Results indicate that K753E has similar profile as L755S mutant for lapatinib. The interacting residues were also found different from other three studied forms as revealed by free energy decomposition and ligplot analysis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Drug Resistance, Neoplasm*
Humans
Lapatinib
Molecular Dynamics Simulation
Mutation*
Protein Conformation
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / metabolism*
Quinazolines / chemistry
Quinazolines / metabolism*
Receptor, ErbB-2 / chemistry*
Receptor, ErbB-2 / genetics
Receptor, ErbB-2 / metabolism*
Signal Transduction

Substances

Protein Kinase Inhibitors
Quinazolines
Lapatinib
ERBB2 protein, human
Receptor, ErbB-2

Grants and funding

This study was funded in part by DST PURSE Grant from Jawaharlal Nehru University in the form of support for the article's publication fee. SG received support from from the Department of Health Research (DHR), India, in the form of the Young Scientist Fellowship. SV received support from the Council of Scientific and Industrial Research (CSIR), India, in the form of a Senior Research Associateship (pool scientist scheme). No additional funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.