Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, oncogenesis, and HER2 inhibitor sensitivity

Hanker, Ariella B.; Brown, Benjamin P.; Meiler, Jens; Marín, Arnaldo; Jayanthan, Harikrishna Sekar; Ye, Dan; Lin, Chang‐Ching; Akamatsu, Hiroaki; Lee, Kyung-min; Chatterjee, Sumanta; Sudhan, Dhivya R.; Servetto, Alberto; Brewer, Monica Red; Koch, James P.; Sheehan, Jonathan H.; He, Jie; Lalani, Alshad S.; Arteaga, Carlos L.

doi:10.1016/j.ccell.2021.06.001

Cited by 56 publications

(54 citation statements)

References 84 publications

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“…Periodic boundary conditions were applied and the particle mesh Ewald (PME) algorithm was adopted for long-range electrostatics with a switching distance of 10 Å. Hydrogen mass repartitioning was employed on solute atoms to allow an integration time step of 4 fs. Gaussian Accelerated MD (GaMD) simulations Gaussian accelerated MD (GaMD) is an enhanced sampling method that adds a boost potential to the potential energy surface to accelerate transitions between low-energy states (51,67). The dual boost potential scheme was applied to the system in order to enhance conformational sampling (67).…”

Section: Methodsmentioning

confidence: 99%

Allele-specific activation, enzyme kinetics, and inhibitor sensitivities of EGFR exon 19 deletion mutations in lung cancer

Brown

Zhang

Kim

et al. 2022

Preprint

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Oncogenic mutations within the epidermal growth factor receptor (EGFR) are found in 15-30% of all non-small cell lung carcinomas. The term exon 19 deletion (ex19del) is collectively used to refer to more than 20 distinct genomic alterations within exon 19 that comprise the most common EGFR mutation subtype in lung cancer. Despite this heterogeneity, clinical treatment decisions are made irrespective of which EGFR ex19del variant is present within the tumor, and there is a paucity of information regarding how individual ex19del variants influence protein structure and function. Herein, we identify allele-specific functional differences among ex19del variants attributable to recurring sequence and structure motifs. We build all-atom structural models of 60 ex19del variants identified in patients and combine ~400 μs of molecular dynamics simulations with biochemical and biophysical experiments to analyze three ex19del mutations (E746_A750, E746_S752>V, and L747_A750>P). We demonstrate that sequence variation in ex19del alters oncogenic cell growth, dimerization propensity, and tyrosine kinase inhibitor (TKI) sensitivity. We show that in contrast to E746_A750 and E746_S752>V, the L747_A750>P variant forms highly active ligand-independent dimers. E746_S752>V displays the least TKI sensitivity among the variants tested, which enzyme kinetic analysis and TKI inhibition experiments suggest is due to increased ATP Km relative to the common E746_A750 variant. Through these analyses, we propose an expanded framework for interpreting ex19del variants and new considerations for therapeutic intervention.SignificanceEGFR mutations are detected in approximately 30% of all lung adenocarcinomas, and the most common EGFR mutation occurring in ~50% of patients is termed “exon 19 deletion” (ex19del). Despite the existence of dozens of different genomic variants comprising what is generically referred to clinically as ex19del, clinicians currently do not distinguish between ex19del variants in considering treatment options, and the differences between ex19del variants are largely unstudied in the broader scientific community. Herein, we describe functional differences between distinct EGFR ex19del variants attributable to the structural features of each variant. These findings suggest a possible explanation for observed differences in patient outcomes stratified by ex19del subtype and reinforce the need for allele-specific considerations in clinical treatment decision making.

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Section: Methodsmentioning

confidence: 99%

Allele-specific activation, enzyme kinetics, and inhibitor sensitivities of EGFR exon 19 deletion mutations in lung cancer

Brown

Zhang

Kim

et al. 2022

Preprint

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“…The idea is that sometimes users know or have predicted with some degree of certainty a chemically meaningful or bioactive pose of a small molecule, but additional refinement is needed. This is a common use case when modeling protein-ligand complexes starting with another ligand with some similarity to the ligand of interest ( Bozhanova et al, 2021 ; Hanker et al, 2021 ). When using pre-generated conformers for docking or small molecule flexible alignment, it is unlikely that the best ligand conformer will be chosen and simultaneously have its position fully optimized in Cartesian space.…”

Section: Small Molecule Conformer Generationmentioning

confidence: 99%

Introduction to the BioChemical Library (BCL): An Application-Based Open-Source Toolkit for Integrated Cheminformatics and Machine Learning in Computer-Aided Drug Discovery

Brown

Geanes

et al. 2022

Front. Pharmacol.

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The BioChemical Library (BCL) cheminformatics toolkit is an application-based academic open-source software package designed to integrate traditional small molecule cheminformatics tools with machine learning-based quantitative structure-activity/property relationship (QSAR/QSPR) modeling. In this pedagogical article we provide a detailed introduction to core BCL cheminformatics functionality, showing how traditional tasks (e.g., computing chemical properties, estimating druglikeness) can be readily combined with machine learning. In addition, we have included multiple examples covering areas of advanced use, such as reaction-based library design. We anticipate that this manuscript will be a valuable resource for researchers in computer-aided drug discovery looking to integrate modular cheminformatics and machine learning tools into their pipelines.

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“…Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that has shown activity in HER2-mutant cancers. 9 Hanker et al published 10 an interesting article in Cancer Cell showing how mutant HER3 receptor cooperates with mutant HER2 to promote tumor growth via enhanced HER2 and phosphoinositide-3-kinase (PI3K) activation. Mutations in HER2 and HER3 showed a significant tendency to cooccur in breast cancers.…”

Section: Co-occurring Gain-of-function Mutations In Her2 and Her3 Modulate Her2/her3 Activation Oncogenesis And Her2 Inhibitor Sensitivitmentioning

confidence: 99%

In the literature: August 2021

et al. 2021

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Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, oncogenesis, and HER2 inhibitor sensitivity

Cited by 56 publications

References 84 publications

Allele-specific activation, enzyme kinetics, and inhibitor sensitivities of EGFR exon 19 deletion mutations in lung cancer

Allele-specific activation, enzyme kinetics, and inhibitor sensitivities of EGFR exon 19 deletion mutations in lung cancer

Introduction to the BioChemical Library (BCL): An Application-Based Open-Source Toolkit for Integrated Cheminformatics and Machine Learning in Computer-Aided Drug Discovery

In the literature: August 2021

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