L718Q mutant EGFR escapes covalent inhibition by stabilizing a non-reactive conformation of the lung cancer drug osimertinib † †Electronic supplementary information (ESI) available: p K a  shift for Cys797; geometries of TSs identified with QM/MM calculations; analysis of the minimum free-energy path for Cys797 alkylation; analysis of MD replicas; convergence for US simulations; replica of simulation of Cys797 alkylation; conformational FESs obtained from each MD replica. See DOI:  10.1039/c7sc04761d

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Abstract

Impact of L718Q mutation on the inhibitory activity of osimertinib on EGFR revealed by free-energy simulations.

Abstract

Osimertinib is a third-generation inhibitor approved for the treatment of non-small cell lung cancer. It overcomes resistance to first-generation inhibitors by incorporating an acrylamide group which alkylates Cys797 of EGFR T790M. The mutation of a residue in the P-loop (L718Q) was shown to cause resistance to osimertinib, but the molecular mechanism of this process is unknown. Here, we investigated the inhibitory process for EGFR T790M (susceptible to osimertinib) and EGFR T790M/L718Q (resistant to osimertinib), by modelling the chemical step ( i.e., alkylation of Cys797) using QM/MM simulations and the recognition step by MD simulations coupled with free-energy calculations. The calculations indicate that L718Q has a negligible impact on both the activation energy for Cys797 alkylation and the free-energy of binding for the formation of the non-covalent complex. The results show that Gln718 affects the conformational space of the EGFR–osimertinib complex, stabilizing a conformation of acrylamide which prevents reaction with Cys797.

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H++ 3.0: automating pK prediction and the preparation of biomolecular structures for atomistic molecular modeling and simulations

Ramu Anandakrishnan, Boris Aguilar, Alexey V. Onufriev (2012)

The accuracy of atomistic biomolecular modeling and simulation studies depend on the accuracy of the input structures. Preparing these structures for an atomistic modeling task, such as molecular dynamics (MD) simulation, can involve the use of a variety of different tools for: correcting errors, adding missing atoms, filling valences with hydrogens, predicting pK values for titratable amino acids, assigning predefined partial charges and radii to all atoms, and generating force field parameter/topology files for MD. Identifying, installing and effectively using the appropriate tools for each of these tasks can be difficult for novice and time-consuming for experienced users. H++ (http://biophysics.cs.vt.edu/) is a free open-source web server that automates the above key steps in the preparation of biomolecular structures for molecular modeling and simulations. H++ also performs extensive error and consistency checking, providing error/warning messages together with the suggested corrections. In addition to numerous minor improvements, the latest version of H++ includes several new capabilities and options: fix erroneous (flipped) side chain conformations for HIS, GLN and ASN, include a ligand in the input structure, process nucleic acid structures and generate a solvent box with specified number of common ions for explicit solvent MD.

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Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor.

Joseph C. Mellor, Amy B. Hill, Michael L James … (2014)

Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.

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LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both.

Katsuyuki Kiura, Kunihiko Koboyashi, Koichi Goto … (2013)

New molecular targeted agents are needed for patients with non-small-cell lung cancer (NSCLC) who progress while receiving erlotinib, gefitinib, or both. Afatinib, an oral irreversible ErbB family blocker, has preclinical activity in epidermal growth factor receptor (EGFR [ErbB1]) mutant models with EGFR-activating mutations, including T790M. This was a Japanese single-arm phase II trial conducted in patients with stage IIIB to IV pulmonary adenocarcinoma who progressed after ≥ 12 weeks of prior erlotinib and/or gefitinib. Patients received afatinib 50 mg per day. The primary end point was objective response rate (complete response or partial response) by independent review. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. Of 62 treated patients, 45 (72.6%) were EGFR mutation positive in their primary tumor according to local and/or central laboratory analyses. Fifty-one patients (82.3%) fulfilled the criteria of acquired resistance to erlotinib and/or gefitinib. Of 61 evaluable patients, five (8.2%; 95% CI, 2.7% to 18.1%) had a confirmed objective response rate (partial response). Median PFS was 4.4 months (95% CI, 2.8 to 4.6 months), and median OS was 19.0 months (95% CI, 14.9 months to not achieved). Two patients had acquired T790M mutations: L858R + T790M, and deletion in exon 19 + T790M; they had stable disease for 9 months and 1 month, respectively. The most common afatinib-related adverse events (AEs) were diarrhea (100%) and rash/acne (91.9%). Treatment-related AEs leading to afatinib discontinuation were experienced by 18 patients (29%), of whom four also had progressive disease. Afatinib demonstrated modest but noteworthy efficacy in patients with NSCLC who had received third- or fourth-line treatment and who progressed while receiving erlotinib and/or gefitinib, including those with acquired resistance to erlotinib, gefitinib, or both.

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Author and article information

Journal

Journal ID (nlm-ta): Chem Sci

Journal ID (iso-abbrev): Chem Sci

Title: Chemical Science

Publisher: Royal Society of Chemistry

ISSN (Print): 2041-6520

ISSN (Electronic): 2041-6539

Publication date (Electronic): 12 February 2018

Publication date Collection: 14 March 2018

Volume: 9

Issue: 10

Pages: 2740-2749

Affiliations

[a ] Department of Food and Drug , University of Parma , Parma , Italy . Email: alessio.lodola@ 123456unipr.it

[b ] School of Chemistry , University of Bristol , Bristol , UK

[c ] Medical Oncology Unit , University Hospital of Parma , Parma , Italy

Author information

D. Callegari http://orcid.org/0000-0002-2574-3826

K. E. Ranaghan http://orcid.org/0000-0002-6391-6601

C. J. Woods http://orcid.org/0000-0001-6563-9903

R. Minari http://orcid.org/0000-0002-4808-0308

M. Tiseo http://orcid.org/0000-0002-9553-8465

M. Mor http://orcid.org/0000-0003-0199-1849

A. Lodola http://orcid.org/0000-0002-8675-1002

Article

Publisher ID: c7sc04761d

DOI: 10.1039/c7sc04761d

PMC ID: 5911825

PubMed ID: 29732058

SO-VID: c05a29a3-3789-4997-a6a6-dac390016d9e

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This article is freely available. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (CC BY 3.0)

History

Date received : 3 November 2017

Date accepted : 3 February 2018

Notes

†Electronic supplementary information (ESI) available: p K _a shift for Cys797; geometries of TSs identified with QM/MM calculations; analysis of the minimum free-energy path for Cys797 alkylation; analysis of MD replicas; convergence for US simulations; replica of simulation of Cys797 alkylation; conformational FESs obtained from each MD replica. See DOI: 10.1039/c7sc04761d

Data availability:

L718Q mutant EGFR escapes covalent inhibition by stabilizing a non-reactive conformation of the lung cancer drug osimertinib†

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Most cited references 32

H++ 3.0: automating pK prediction and the preparation of biomolecular structures for atomistic molecular modeling and simulations

Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor.

LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both.

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