Cells

Editorial

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3 pages, 183 KiB

Open AccessEditorial

EGFR Signaling in Non-Small Cell Lung Cancer: From Molecular Mechanisms to Therapeutic Opportunities

by Silvia La Monica

Cells 2022, 11(8), 1344; https://doi.org/10.3390/cells11081344 - 14 Apr 2022

Cited by 1 | Viewed by 1362

Abstract

Lung cancer is the leading cause of cancer death worldwide [...] Full article

(This article belongs to the Special Issue EGFR Signaling in Non-Small-Cell Lung Cancer: From Molecular Mechanisms to Therapeutic Opportunities)

Research

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13 pages, 3055 KiB

Open AccessArticle

Liquid Biopsy for Disease Monitoring in Non-Small Cell Lung Cancer: The Link between Biology and the Clinic

by Maria Gabriela O. Fernandes, Catarina Sousa, Joana Pereira Reis, Natália Cruz-Martins, Conceição Souto Moura, Susana Guimarães, Ana Justino, Maria João Pina, Adriana Magalhães, Henrique Queiroga, José Agostinho Marques, José Carlos Machado, José Luís Costa and Venceslau Hespanhol

Cells 2021, 10(8), 1912; https://doi.org/10.3390/cells10081912 - 28 Jul 2021

Cited by 11 | Viewed by 2624

Abstract

Introduction: Cell-free DNA (cfDNA) analysis offers a non-invasive method to identify sensitising and resistance mutations in advanced Non-Small Cell Lung Cancer (NSCLC) patients. Next-generation sequencing (NGS) of circulating free DNA (cfDNA) is a valuable tool for mutations detection and disease′s clonal monitoring. Material [...] Read more.

Introduction: Cell-free DNA (cfDNA) analysis offers a non-invasive method to identify sensitising and resistance mutations in advanced Non-Small Cell Lung Cancer (NSCLC) patients. Next-generation sequencing (NGS) of circulating free DNA (cfDNA) is a valuable tool for mutations detection and disease′s clonal monitoring. Material and methods: An amplicon-based targeted gene NGS panel was used to analyse 101 plasma samples of advanced non-small cell lung cancer (NSCLC) patients with known oncogenic mutations, mostly EGFR mutations, serially collected at different clinically relevant time points of the disease. Results: The variant allelic frequency (VAF) monitoring in consecutive plasma samples demonstrated different molecular response and progression patterns. The decrease in or the clearance of the mutant alleles was associated with response and the increase in or the emergence of novel alterations with progression. At the best response, the median VAF was 0% (0.0% to 3.62%), lower than that at baseline, with a median of 0.53% (0.0% to 9.9%) (p = 0.004). At progression, the VAF was significantly higher (median 4.67; range: 0.0–36.9%) than that observed at the best response (p = 0.001) and baseline (p = 0.006). These variations anticipated radiographic changes in most cases, with a median time of 0.86 months. Overall, the VAF evolution of different oncogenic mutations predicts clinical outcomes. Conclusion: The targeted NGS of circulating tumour DNA (ctDNA) has clinical utility to monitor treatment response in patients with advanced lung adenocarcinoma. Full article

(This article belongs to the Special Issue EGFR Signaling in Non-Small-Cell Lung Cancer: From Molecular Mechanisms to Therapeutic Opportunities)

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15 pages, 1743 KiB

Open AccessFeature PaperArticle

Dynamic Evaluation of Circulating miRNA Profile in EGFR-Mutated NSCLC Patients Treated with EGFR-TKIs

by Alessandro Leonetti, Mjriam Capula, Roberta Minari, Giulia Mazzaschi, Alessandro Gregori, Btissame El Hassouni, Filippo Papini, Paola Bordi, Michela Verzè, Amir Avan, Marcello Tiseo and Elisa Giovannetti

Cells 2021, 10(6), 1520; https://doi.org/10.3390/cells10061520 - 16 Jun 2021

Cited by 9 | Viewed by 2101

Abstract

Background: Resistance to EGFR-TKIs constitutes a major challenge for the management of EGFR-mutated NSCLC, and recent evidence suggests that deregulation of specific microRNAs (miRNAs) may influence resistance to targeted agents. In this retrospective study, we explored the role of specific plasmatic miRNAs [...] Read more.

Background: Resistance to EGFR-TKIs constitutes a major challenge for the management of EGFR-mutated NSCLC, and recent evidence suggests that deregulation of specific microRNAs (miRNAs) may influence resistance to targeted agents. In this retrospective study, we explored the role of specific plasmatic miRNAs (miR-21, miR-27a and miR-181a) as a surrogate for predicting EGFR-TKI performance in EGFR-mutated NSCLC patients. Methods: Plasma samples of 39 advanced EGFR-mutated NSCLC patients treated with EGFR-TKIs were collected at different points in time and miRNA levels were assessed by RT-PCR. Results: Higher basal values of miR-21 were reported in patients who achieved a partial/complete response (PR/CR) compared to those with stability/progression of disease (SD/PD) (p = 0.011). Along the same line, patients who experienced a clinical benefit lasting at least six months displayed higher basal levels of circulating miR-21 (p = 0.039). However, dynamic evaluation of miRNA values after two months from the start of EGFR-TKI treatment showed that patients who experienced SD had an increase in miR-21 levels (Fold Change [FC] = 2.6) compared to patients achieving PR/CR (p = 0.029). The same tendency was observed for miR-27a (FC = 3.1) and miR-181a (FC = 2.0), although without reaching statistical significance. Remarkably, preclinical studies showed an increase in miR-21 levels in NSCLC cells that became resistant after exposure to EGFR-TKIs. Conclusions: Our study provides interesting insights on the role of circulating miRNAs, in particular miR-21, and their dynamic change over time in predicting EGFR-TKI response in EGFR-mutated NSCLC. Full article

(This article belongs to the Special Issue EGFR Signaling in Non-Small-Cell Lung Cancer: From Molecular Mechanisms to Therapeutic Opportunities)

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Review

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19 pages, 1921 KiB

Open AccessReview

Reprogramming of Lipid Metabolism in Lung Cancer: An Overview with Focus on EGFR-Mutated Non-Small Cell Lung Cancer

by Kamal Eltayeb, Silvia La Monica, Marcello Tiseo, Roberta Alfieri and Claudia Fumarola

Cells 2022, 11(3), 413; https://doi.org/10.3390/cells11030413 - 25 Jan 2022

Cited by 28 | Viewed by 6562

Abstract

Lung cancer is the leading cause of cancer deaths worldwide. Most of lung cancer cases are classified as non-small cell lung cancers (NSCLC). EGFR has become an important therapeutic target for the treatment of NSCLC patients, and inhibitors targeting the kinase domain of [...] Read more.

Lung cancer is the leading cause of cancer deaths worldwide. Most of lung cancer cases are classified as non-small cell lung cancers (NSCLC). EGFR has become an important therapeutic target for the treatment of NSCLC patients, and inhibitors targeting the kinase domain of EGFR are currently used in clinical settings. Recently, an increasing interest has emerged toward understanding the mechanisms and biological consequences associated with lipid reprogramming in cancer. Increased uptake, synthesis, oxidation, or storage of lipids has been demonstrated to contribute to the growth of many types of cancer, including lung cancer. In this review, we provide an overview of metabolism in cancer and then explore in more detail the role of lipid metabolic reprogramming in lung cancer development and progression and in resistance to therapies, emphasizing its connection with EGFR signaling. In addition, we summarize the potential therapeutic approaches targeting lipid metabolism for lung cancer treatment. Full article

(This article belongs to the Special Issue EGFR Signaling in Non-Small-Cell Lung Cancer: From Molecular Mechanisms to Therapeutic Opportunities)

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25 pages, 1509 KiB

Open AccessReview

Emerging Molecular Dependencies of Mutant EGFR-Driven Non-Small Cell Lung Cancer

by Dylan A. Farnsworth, Yankuan T. Chen, Georgia de Rappard Yuswack and William W. Lockwood

Cells 2021, 10(12), 3553; https://doi.org/10.3390/cells10123553 - 16 Dec 2021

Cited by 6 | Viewed by 5143

Abstract

Epidermal growth factor receptor (EGFR) mutations are the molecular driver of a subset of non-small cell lung cancers (NSCLC); tumors that harbor these mutations are often dependent on sustained oncogene signaling for survival, a concept known as “oncogene addiction”. Inhibiting EGFR with tyrosine [...] Read more.

Epidermal growth factor receptor (EGFR) mutations are the molecular driver of a subset of non-small cell lung cancers (NSCLC); tumors that harbor these mutations are often dependent on sustained oncogene signaling for survival, a concept known as “oncogene addiction”. Inhibiting EGFR with tyrosine kinase inhibitors has improved clinical outcomes for patients; however, successive generations of inhibitors have failed to prevent the eventual emergence of resistance to targeted agents. Although these tumors have a well-established dependency on EGFR signaling, there remain questions about the underlying genetic mechanisms necessary for EGFR-driven oncogenesis and the factors that allow tumor cells to escape EGFR dependence. In this review, we highlight the latest findings on mutant EGFR dependencies, co-operative drivers, and molecular mechanisms that underlie sensitivity to EGFR inhibitors. Additionally, we offer perspective on how these discoveries may inform novel combination therapies tailored to EGFR mutant NSCLC. Full article

(This article belongs to the Special Issue EGFR Signaling in Non-Small-Cell Lung Cancer: From Molecular Mechanisms to Therapeutic Opportunities)

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14 pages, 1125 KiB

Open AccessFeature PaperReview

Anticipating EGFR Targeting in Early Stages of Lung Cancer: Leave No Stone Unturned

by Lorenzo Belluomini, Silvia Teresa Riva, Michele Simbolo, Riccardo Nocini, Ilaria Trestini, Alice Avancini, Daniela Tregnago, Miriam Grazia Ferrara, Alberto Caldart, Alessandra Dodi, Anna Caliò, Emilio Bria, Aldo Scarpa, Michele Milella, Jessica Menis and Sara Pilotto

Cells 2021, 10(10), 2685; https://doi.org/10.3390/cells10102685 - 7 Oct 2021

Cited by 5 | Viewed by 2711

Abstract

Background: The current treatment landscape of early stage lung cancer is rapidly evolving, particularly in EGFR mutant non-small cell lung cancer (NSCLC), where target therapy is moving to early stages. In the current review, we collected the available data exploring the impact [...] Read more.

Background: The current treatment landscape of early stage lung cancer is rapidly evolving, particularly in EGFR mutant non-small cell lung cancer (NSCLC), where target therapy is moving to early stages. In the current review, we collected the available data exploring the impact of EGFR targeting in both neoadjuvant and adjuvant settings, underlying lights and shadows and discussing the existing open issues. Methods: We performed a comprehensive search using PubMed and the proceedings of major international meetings to identify neoadjuvant/adjuvant trials with EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. Results: Limited data are available so far about the activity/efficacy of neoadjuvant TKIs in EGFR mutant NSCLC, with only modest downstaging and pathological complete response rates reported. Differently, the ADAURA trial already proposed osimertinib as a potential new standard of care in resected NSCLC harboring an activating EGFR mutation. Conclusion: Anticipating targeted therapy to early stage EGFR mutant NSCLC presents great opportunities but also meaningful challenges in the current therapeutic/diagnostic pathway of lung cancer care. Appropriate endpoint(s) selection for clinical trials, disease progression management, patients’ and treatment selection, as well as need to address the feasibility of molecular profiling anticipation, represent crucial issues to face before innovation can move to early stages. Full article

(This article belongs to the Special Issue EGFR Signaling in Non-Small-Cell Lung Cancer: From Molecular Mechanisms to Therapeutic Opportunities)

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11 pages, 1932 KiB

Open AccessReview

Drug Tolerance to EGFR Tyrosine Kinase Inhibitors in Lung Cancers with EGFR Mutations

by Kenichi Suda and Tetsuya Mitsudomi

Cells 2021, 10(7), 1590; https://doi.org/10.3390/cells10071590 - 24 Jun 2021

Cited by 16 | Viewed by 3316

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) serve as the standard of care for the first-line treatment of patients with lung cancers with EGFR-activating mutations. However, the acquisition of resistance to EGFR TKIs is almost inevitable, with extremely rare exceptions, [...] Read more.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) serve as the standard of care for the first-line treatment of patients with lung cancers with EGFR-activating mutations. However, the acquisition of resistance to EGFR TKIs is almost inevitable, with extremely rare exceptions, and drug-tolerant cells (DTCs) that demonstrate reversible drug insensitivity and that survive the early phase of TKI exposure are hypothesized to be an important source of cancer cells that eventually acquire irreversible resistance. Numerous studies on the molecular mechanisms of drug tolerance of EGFR-mutated lung cancers employ lung cancer cell lines as models. Here, we reviewed these studies to generally describe the features, potential origins, and candidate molecular mechanisms of DTCs. The rapid development of an optimal treatment for EGFR-mutated lung cancer will require a better understanding of the underlying molecular mechanisms of the drug insensitivity of DTCs. Full article

(This article belongs to the Special Issue EGFR Signaling in Non-Small-Cell Lung Cancer: From Molecular Mechanisms to Therapeutic Opportunities)

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24 pages, 2830 KiB

Open AccessReview

Epidermal Growth Factor Receptor Expression and Resistance Patterns to Targeted Therapy in Non-Small Cell Lung Cancer: A Review

by Emma-Anne Karlsen, Sam Kahler, Joan Tefay, Shannon R. Joseph and Fiona Simpson

Cells 2021, 10(5), 1206; https://doi.org/10.3390/cells10051206 - 14 May 2021

Cited by 17 | Viewed by 4648

Abstract

Globally, lung cancer is the leading cause of cancer-related death. The majority of non-small cell lung cancer (NSCLC) tumours express epidermal growth factor receptor (EGFR), which allows for precise and targeted therapy in these patients. The dysregulation of EGFR in solid epithelial cancers [...] Read more.

Globally, lung cancer is the leading cause of cancer-related death. The majority of non-small cell lung cancer (NSCLC) tumours express epidermal growth factor receptor (EGFR), which allows for precise and targeted therapy in these patients. The dysregulation of EGFR in solid epithelial cancers has two distinct mechanisms: either a kinase-activating mutation in EGFR (EGFR-mutant) and/or an overexpression of wild-type EGFR (wt-EGFR). The underlying mechanism of EGFR dysregulation influences the efficacy of anti-EGFR therapy as well as the nature of resistance patterns and secondary mutations. This review will critically analyse the mechanisms of EGFR expression in NSCLC, its relevance to currently approved targeted treatment options, and the complex nature of secondary mutations and intrinsic and acquired resistance patterns in NSCLC. Full article

(This article belongs to the Special Issue EGFR Signaling in Non-Small-Cell Lung Cancer: From Molecular Mechanisms to Therapeutic Opportunities)

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Other

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13 pages, 625 KiB

Open AccessPerspective

OPALS: A New Osimertinib Adjunctive Treatment of Lung Adenocarcinoma or Glioblastoma Using Five Repurposed Drugs

by Richard E. Kast, Marc-Eric Halatsch and Rafael Rosell

Cells 2021, 10(5), 1148; https://doi.org/10.3390/cells10051148 - 10 May 2021

Cited by 3 | Viewed by 3791

Abstract

Background: Pharmacological targeting aberrant activation of epidermal growth factor receptor tyrosine kinase signaling is an established approach to treating lung adenocarcinoma. Osimertinib is a tyrosine kinase approved and effective in treating lung adenocarcinomas that have one of several common activating mutations in epidermal [...] Read more.

Background: Pharmacological targeting aberrant activation of epidermal growth factor receptor tyrosine kinase signaling is an established approach to treating lung adenocarcinoma. Osimertinib is a tyrosine kinase approved and effective in treating lung adenocarcinomas that have one of several common activating mutations in epidermal growth factor receptor. The emergence of resistance to osimertinib after a year or two is the rule. We developed a five-drug adjuvant regimen designed to increase osimertinib’s growth inhibition and thereby delay the development of resistance. Areas of Uncertainty: Although the assembled preclinical data is strong, preclinical data and the following clinical trial results can be discrepant. The safety of OPALS drugs when used individually is excellent. We have no data from humans on their tolerability when used as an ensemble. That there is no data from the individual drugs to suspect problematic interaction does not exclude the possibility. Data Sources: All relevant PubMed.org articles on the OPALS drugs and corresponding pathophysiology of lung adenocarcinoma and glioblastoma were reviewed. Therapeutic Opinion: The five drugs of OPALS are in wide use in general medicine for non-oncology indications. OPALS uses the anti-protozoal drug pyrimethamine, the antihistamine cyproheptadine, the antibiotic azithromycin, the antihistamine loratadine, and the potassium sparing diuretic spironolactone. We show how these inexpensive and generically available drugs intersect with and inhibit lung adenocarcinoma growth drive. We also review data showing that both OPALS adjuvant drugs and osimertinib have data showing they may be active in suppressing glioblastoma growth. Full article

(This article belongs to the Special Issue EGFR Signaling in Non-Small-Cell Lung Cancer: From Molecular Mechanisms to Therapeutic Opportunities)

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