scholarly journals Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Jacob J. Chabon ◽  
Andrew D. Simmons ◽  
Alexander F. Lovejoy ◽  
Mohammad S. Esfahani ◽  
Aaron M. Newman ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Resistance Mechanism ◽  
Growth Factor Receptor ◽  
Resistance Mechanisms ◽  
Egfr Inhibitor ◽  
Tumour Heterogeneity ◽  
Lung Cancer Patients ◽  
Ctdna Analysis ◽  
Inhibitor Resistance ◽  
Circulating Tumour Dna

Abstract Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment.

scholarly journals Genotype-determined EGFR-RTK heterodimerization and its effects on drug resistance in lung Cancer treatment revealed by molecular dynamics simulations

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Mengxu Zhu ◽  
Debby D. Wang ◽  
Hong Yan
Keyword(s):  
Lung Cancer ◽  
Molecular Dynamics ◽  
Drug Resistance ◽  
Center Of Mass ◽  
Resistance Mechanism ◽  
Growth Factor Receptor ◽  
Resistant Mutant ◽  
Resistance Mechanisms ◽  
Egfr Mutations ◽  
Geometrical Properties

Abstract Background Epidermal growth factor receptor (EGFR) and its signaling pathways play a vital role in pathogenesis of lung cancer. By disturbing EGFR signaling, mutations of EGFR may lead to progression of cancer or the emergence of resistance to EGFR-targeted drugs. Results We investigated the correlation between EGFR mutations and EGFR-receptor tyrosine kinase (RTK) crosstalk in the signaling network, in order to uncover the drug resistance mechanism induced by EGFR mutations. For several EGFR wild type (WT) or mutated proteins, we measured the EGFR-RTK interactions using several computational methods based on molecular dynamics (MD) simulations, including geometrical characterization of the interfaces and conventional estimation of free energy of binding. Geometrical properties, namely the matching rate of atomic solid angles in the interfaces and center-of-mass distances between interacting atoms, were extracted relying on Alpha Shape modeling. For a couple of RTK partners (c-Met, ErbB2 and IGF-1R), results have shown a looser EGFR-RTK crosstalk for the drug-sensitive EGFR mutant while a tighter crosstalk for the drug-resistant mutant. It guarantees the genotype-determined EGFR-RTK crosstalk, and further proposes a potential drug resistance mechanism by amplified EGFR-RTK crosstalk induced by EGFR mutations. Conclusions This study will lead to a deeper understanding of EGFR mutation-induced drug resistance mechanisms and promote the design of innovative drugs.

Incidence of Adverse Cutaneous Reactions to Epidermal Growth Factor Receptor Inhibitors in Patients with Non-Small-Cell Lung Cancer

Dermatology ◽  
2021 ◽  
pp. 1-5
Author(s):  
Paolo Gisondi ◽  
Davide Geat ◽  
Alessandra Mattiucci ◽  
Fiorella Lombardo ◽  
Antonio Santo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Egfr Inhibitor ◽  
Small Cell Lung ◽  
Nail Changes ◽  
Cutaneous Reactions ◽  
Epidermal Growth ◽  
Oncologic Treatment

<b><i>Background:</i></b> Epidermal growth factor receptor (EGFR) inhibitors are routinely used in advanced non-small-cell lung cancer (NSCLC) harboring EGFR mutations. However, their use is associated with gastrointestinal and cutaneous toxicities, including acneiform eruptions, pruritus, xerosis, nail and hair changes. Aside from reducing patients’ quality of life, such cutaneous reactions have a considerable impact on the oncologic treatment given that dose reduction or even drug discontinuation may be necessary, especially for the severe forms. <b><i>Objectives:</i></b> To assess the incidence, impact on treatment and management of EGFR inhibitor-related cutaneous reactions in patients with NSCLC. <b><i>Methods:</i></b> We conducted a prospective observational study on 87 consecutive patients with advanced NSCLC treated with EGFR-tyrosine kinase inhibitors from January to December 2019. Patients who developed mucocutaneous reactions were evaluated and treated by both oncologists and dermatologists, and underwent dermatologic follow-up until resolution of the cutaneous reaction. Demographic and clinical data were collected for each patient, and the severity of the cutaneous reaction was graded using the Common Terminology Criteria for Adverse Events. <b><i>Results:</i></b> Seventy-one patients (81.6%) developed cutaneous reactions. The number of cutaneous reactions per patient was 1 in 37%, 2 in 41% and 3 or more in 22%. The most common cutaneous reactions included acneiform eruptions (56.3%), xerosis ± asteatotic eczema (48.3%), nail changes (39.1%), mucositis (29.9%), pruritus (24.1%) and hair changes (12.6%). Afatinib was associated with a higher rate of nail changes and mucositis (<i>p</i> &#x3c; 0.01 and <i>p</i> &#x3c; 0.005, respectively) compared to other agents, while no patient-related predictive factors were identified. Dose reduction was performed in 18% of patients. Multidisciplinary management involving dermatologists allowed to resume the drug in all patients who had discontinued it due to the cutaneous reactions. <b><i>Conclusions:</i></b> A multidisciplinary approach to EGFR inhibitor-related cutaneous reactions is advantageous and can reduce the need to discontinue oncologic treatment.

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