Hope and Disappointment: Covalent Inhibitors to Overcome Drug Resistance in Non-Small Cell Lung Cancer

Abstract

In the last five years, the detailed understanding of how to overcome T790M drug resistance in non-small cell lung cancer (NSCLC) has culminated in the development of a third-generation of covalent EGFR inhibitors with excellent clinical outcomes. However, the emergence of a newly discovered acquired drug resistance challenges the concept of small molecule targeted cancer therapy in NSCLC.

Figure 1

(A) Chemical structures of representative examples of the three generations of EGFR inhibitors currently used in the treatment of NSCLC. The reactive acrylamides are highlighted in green. (B) Illustration of the steric repulsion of the first-generation inhibitor gefitinib upon T790M gatekeeper mutation. The gefitinib binding pose observed with EGFR wild type (white, PDB code: 2ITY) would lead to a steric clash with the methionine side chain (blue, PDB code: 3UG1), resulting in an unfavored binding pose (pink, PDB code: 3UG2).

Figure 2

Binding mode of covalent EGFR tyrosine kinase inhibitors. The binding equilibrium indicates, whether the binding of ligand (L) and receptor (R) is favored. (A) The emergence of the T790M gatekeeper mutation induces steric hindrance of 4-aminoquinazolines such as afatinib with the methionine side chain (highlighted in red) and promotes the dissociation of the reversible ligand and receptor complex [LR]. Therefore, covalent bond formation (highlighted in yellow) of second-generation inhibitors with the receptor, yielding the covalent adduct L–R, cannot sufficiently occur (PDB code: 4G5P). (B) Third-generation TKIs, as exemplified by the structural analogue WZ4002, avoid the steric conflict with Met790 and therefore achieve complete receptor occupancy (PDB code: 3IKA). (C) The C797S mutation mediates resistance to irreversible drugs since the less nucleophilic serine side chain cannot undergo covalent bond formation (highlighted in red) at physiological conditions (model based on PDB code: 3IKA).