Electrostatic explanation of D1228V/H/N-induced c-Met resistance and sensitivity to type I and type II kinase inhibitors in targeted gastric cancer therapy
- 20 Downloads
The c-Met D1228V/H/N mutation clinically causes acquired resistance to type I tyrosine kinase inhibitors (TKIs), while maintaining sensitivity to type II TKIs in targeted gastric cancer therapy. The mutation is located in the activation loop (A-loop) region of the c-Met kinase domain, which substitutes the negatively charged residue Asp1228 with electroneutral amino acid Val, His, or Asn, thus electrostatically destabilizing the DFG-in conformation of A-loop and inducing its transition to DFG-out state. The transition is spontaneous in a dynamics point of view and the A-loop exhibits a large intrinsic disorder during the transitional dynamics course. In DFG-in conformation, the wild-type Asp1228 is surrounded by a number of positively charged residues within its first and second shells, which can also form a hydrogen-bonding network with its vicinal residues Phe1089, Lys1110, Asp1222, and Met1229 in the first shell. Type I and type II TKIs respond oppositely to the mutation; the former shows a generic resistance to the mutation, whereas the latter is generally sensitized by the mutation. Both types of TKIs do not directly interact with the mutation. Instead, the mutation-induced conformational change in A-loop reshapes kinase active site and then influences the site interactions with inhibitor ligands, thus conferring different selectivity to the type I and type II TKIs.
Keywordsc-Met kinase D1228V/H/N mutation Tyrosine kinase inhibitor Acquired resistance Targeted gastric cancer therapy Electrostatic stability Molecular dynamics
This work was supported by the Social Development Fund of Zhenjiang (No. SH2015069) and the Clinical Medicine Development Project of Jiangsu University (No. JLY20160104).
Compliance with ethical standards
Conflict of interest
The authors report no declarations of interest.
- 12.Engstrom LD, Aranda R, Lee M, Tovar EA, Essenburg CJ, Madaj Z, Chiang H, Briere D, Hallin J, Lopez-Casas PP, Baños N, Menendez C, Hidalgo M, Tassell V, Chao R, Chudova DI, Lanman RB, Olson P, Bazhenova L, Patel SP, Graveel C, Nishino M, Shapiro GI, Peled N, Awad MM, Jänne PA, Christensen JG (2017) Glesatinib exhibits antitumor activity in lung cancer models and patients harboring MET exon 14 mutations and overcomes mutation-mediated resistance to type I MET inhibitors in nonclinical models. Clin Cancer Res 23:6661–6672CrossRefGoogle Scholar
- 15.Tiedt R, Degenkolbe E, Furet P, Appleton BA, Wagner S, Schoepfer J, Buck E, Ruddy DA, Monahan JE, Jones MD, Blank J, Haasen D, Drueckes P, Wartmann M, McCarthy C, Sellers WR, Hofmann F (2011) A drug resistance screen using a selective MET inhibitor reveals a spectrum of mutations that partially overlap with activating mutations found in cancer patients. Cancer Res 71:5255–5264CrossRefGoogle Scholar
- 25.Luo H, Du T, Zhou P, Yang L, Mei H, Ng H, Zhang W, Shu M, Tong W, Shi L, Mendrick DL, Hong H (2015) Molecular docking to identify associations between drugs and class I human leukocyte antigens for predicting idiosyncratic drug reactions. Comb Chem High Throughput Screen 18:296–304CrossRefGoogle Scholar
- 29.Zhou P, Zhang S, Wang Y, Yang C, Huang J (2016) Structural modeling of HLA-B1502 peptide carbamazepine T-cell receptor complex architecture: implication for the molecular mechanism of carbamazepine-induced Stevens–Johnson syndrome toxic epidermal necrolysis. J Biomol Struct Dyn 34:1806–1817CrossRefGoogle Scholar