scholarly journals Proteogenomic systems analysis identifies targeted therapy resistance mechanisms in EGFR‐mutated lung cancer

2018 ◽  
Vol 144 (3) ◽  
pp. 545-557 ◽  
Author(s):  
Denise Treue ◽  
Michael Bockmayr ◽  
Albrecht Stenzinger ◽  
Daniel Heim ◽  
Svenja Hester ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Systems Analysis ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Egfr Mutated

Treatment in EGFR-mutated Non-small Cell Lung Cancer: How to Block the Receptor and overcome Resistance Mechanisms

2017 ◽  
Vol 103 (4) ◽  
pp. 325-337 ◽  
Author(s):  
Claudia Proto ◽  
Giuseppe Lo Russo ◽  
Giulia Corrao ◽  
Monica Ganzinelli ◽  
Francesco Facchinetti ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Factor Receptor ◽  
Resistance Mechanisms ◽  
Small Cell ◽  
Third Generation ◽  
Small Cell Lung ◽  
Epidermal Growth ◽  
Exon 20 ◽  
Egfr Mutated ◽  
Egfr Tkis

In non-small cell lung cancer (NSCLC), the identification of epidermal growth factor receptor (EGFR) mutations and the parallel development of EGFR tyrosine kinase inhibitors (TKIs) have radically changed the therapeutic management strategies. Currently, erlotinib, gefitinib, and afatinib are all approved as standard first-line treatment in EGFR-mutated NSCLC. However, despite the proven efficacy, some EGFR-mutated NSCLCs do not respond to EGFR TKIs, while some patients, after a favorable and prolonged response to EGFR TKIs, inevitably progress within about 10-14 months. Epidermal growth factor receptor-dependent mechanisms, activation of alternative pathways, or phenotypic transformation can cause the resistance to EGFR TKIs. The exon 20 p.Thr790Met point mutation (T790M) is responsible for about 60% of cases of resistance when progression occurs. A third-generation TKI, osimertinib, improved outcome in patients harboring T790M after first- and second-generation TKI treatment. However, resistance develops even after treatment with third-generation drugs. To date, the Cys797Ser (C797S) mutation in exon 20 of EGFR is the most well-known resistance mutation after osimertinib. Fourth-generation TKIs are already under development. Nevertheless, additional information is needed to better understand and effectively overcome resistance. The aim of this review is to report recent advances and future perspectives in the treatment of EGFR-mutated NSCLC, highlighting the resistance mechanisms that underlie disease progression.

scholarly journals Exploiting vulnerabilities in cancer signalling networks to combat targeted therapy resistance

2018 ◽  
Vol 62 (4) ◽  
pp. 583-593 ◽  
Author(s):  
Peter T. Harrison ◽  
Paul H. Huang
Keyword(s):  
Drug Resistance ◽  
Targeted Therapy ◽  
Kinase Inhibitors ◽  
Effective Means ◽  
Deep Understanding ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Precision Oncology ◽  
First Line ◽  
Clinical Responses

Drug resistance remains one of the greatest challenges facing precision oncology today. Despite the vast array of resistance mechanisms that cancer cells employ to subvert the effects of targeted therapy, a deep understanding of cancer signalling networks has led to the development of novel strategies to tackle resistance both in the first-line and salvage therapy settings. In this review, we provide a brief overview of the major classes of resistance mechanisms to targeted therapy, including signalling reprogramming and tumour evolution; our discussion also focuses on the use of different forms of polytherapies (such as inhibitor combinations, multi-target kinase inhibitors and HSP90 inhibitors) as a means of combating resistance. The promise and challenges facing each of these polytherapies are elaborated with a perspective on how to effectively deploy such therapies in patients. We highlight efforts to harness computational approaches to predict effective polytherapies and the emerging view that exceptional responders may hold the key to better understanding drug resistance. This review underscores the importance of polytherapies as an effective means of targeting resistance signalling networks and achieving durable clinical responses in the era of personalised cancer medicine.

Cell membrane based biomimetic nanocomposites for targeted therapy of drug resistant EGFR-mutated lung cancer

Nanoscale ◽  
2019 ◽  
Vol 11 (41) ◽  
pp. 19520-19528 ◽  
Author(s):  
Pengying Wu ◽  
Dongtao Yin ◽  
Jiaming Liu ◽  
Huige Zhou ◽  
Mengyu Guo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Targeted Therapy ◽  
Cell Membrane ◽  
Cancer Cell ◽  
Egfr Mutation ◽  
Drug Resistant ◽  
Egfr Mutated

A cancer cell membrane-based biomimetic strategy was developed by loading doxorubicin and icotinib to overcome drug-resistance of EGFR-mutation lung cancer.

Detecting resistance in EGFR-mutated non-small-cell lung cancer after clonal selection through targeted therapy

2015 ◽  
Vol 12 (2) ◽  
pp. 63-66 ◽  
Author(s):  
Justine L Kuiper ◽  
Idris Bahce ◽  
Charlotte Voorhoeve ◽  
Maqsood Yaqub ◽  
Daniëlle AM Heideman ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Clonal Selection ◽  
Small Cell ◽  
Small Cell Lung ◽  
Egfr Mutated

Resistance mechanisms to osimertinib in EGFR-mutated advanced non-small-cell lung cancer: A multicentric retrospective French study

Lung Cancer ◽  
2019 ◽  
Vol 137 ◽  
pp. 149-156 ◽  
Author(s):  
Camille Mehlman ◽  
Jacques Cadranel ◽  
Gaelle Rousseau-Bussac ◽  
Roger Lacave ◽  
Anaïs Pujals ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Resistance Mechanisms ◽  
Small Cell ◽  
Small Cell Lung ◽  
French Study ◽  
Egfr Mutated

scholarly journals Emerging insights of tumor heterogeneity and drug resistance mechanisms in lung cancer targeted therapy

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Zuan-Fu Lim ◽  
Patrick C. Ma
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Targeted Therapy ◽  
Minimal Residual Disease ◽  
Tumor Heterogeneity ◽  
Residual Disease ◽  
Resistance Mechanisms ◽  
Intratumoral Heterogeneity ◽  
Acquired Drug Resistance ◽  
Minimal Residual

AbstractThe biggest hurdle to targeted cancer therapy is the inevitable emergence of drug resistance. Tumor cells employ different mechanisms to resist the targeting agent. Most commonly in EGFR-mutant non-small cell lung cancer, secondary resistance mutations on the target kinase domain emerge to diminish the binding affinity of first- and second-generation inhibitors. Other alternative resistance mechanisms include activating complementary bypass pathways and phenotypic transformation. Sequential monotherapies promise to temporarily address the problem of acquired drug resistance, but evidently are limited by the tumor cells’ ability to adapt and evolve new resistance mechanisms to persist in the drug environment. Recent studies have nominated a model of drug resistance and tumor progression under targeted therapy as a result of a small subpopulation of cells being able to endure the drug (minimal residual disease cells) and eventually develop further mutations that allow them to regrow and become the dominant population in the therapy-resistant tumor. This subpopulation of cells appears to have developed through a subclonal event, resulting in driver mutations different from the driver mutation that is tumor-initiating in the most common ancestor. As such, an understanding of intratumoral heterogeneity—the driving force behind minimal residual disease—is vital for the identification of resistance drivers that results from branching evolution. Currently available methods allow for a more comprehensive and holistic analysis of tumor heterogeneity in that issues associated with spatial and temporal heterogeneity can now be properly addressed. This review provides some background regarding intratumoral heterogeneity and how it leads to incomplete molecular response to targeted therapies, and proposes the use of single-cell methods, sequential liquid biopsy, and multiregion sequencing to discover the link between intratumoral heterogeneity and early adaptive drug resistance. In summary, minimal residual disease as a result of intratumoral heterogeneity is the earliest form of acquired drug resistance. Emerging technologies such as liquid biopsy and single-cell methods allow for studying targetable drivers of minimal residual disease and contribute to preemptive combinatorial targeting of both drivers of the tumor and its minimal residual disease cells.

scholarly journals Epigenetics in non-small cell lung carcinomas

2019 ◽  
Vol 61 (3, may-jun) ◽  
pp. 318 ◽  
Author(s):  
Irlanda Peralta-Arrieta ◽  
Leonel Armas-López ◽  
Joaquín Zúñiga ◽  
Federico Ávila-Moreno
Keyword(s):  
Lung Cancer ◽  
Systematic Review ◽  
Molecular Complexes ◽  
Therapy Resistance ◽  
Molecular Study ◽  
Resistance Mechanisms ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cancer Epigenetics ◽  
Lung Carcinomas

Objective. To perform a systematic review of the main epi­genetic aberrations involved in non-small cell lung carcinomas’ (NSCLC) diagnosis, progression, and therapeutics. Materials and methods. We performed a systematic review of the scientific literature on lung cancer epigenetics, focusing on NSCLC. Results. Several advances in the molecular study of classical epigenetic mechanisms and massive studies of lung cancer epigenome have contributed relevant new evidence revealing that various molecular complexes are functionally influencing genetic-epigenetic and transcriptional mechanisms that promote lung tumorigenesis (initiation, promotion, and progression), and are also involved in NSCLC therapy-resistance mechanisms. Conclusion. Several epigenetic complexes and mechanisms must be analyzed and considered for the design of new and efficient therapies, which could be fundamental to develop an integrated knowledge to achieve a comprehensive lung cancer personalized medicine.

Significance of Neutrophil-to-lymphocyte Ratio in Western Advanced EGFR-mutated Non-small Cell Lung Cancer Receiving a Targeted Therapy

2017 ◽  
Vol 103 (5) ◽  
pp. 443-448 ◽  
Author(s):  
Fausto Meriggi ◽  
Claudio Codignola ◽  
Giordano D. Beretta ◽  
Giovanni L. Ceresoli ◽  
Alberto Caprioli ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Neutrophil To Lymphocyte Ratio ◽  
Small Cell Lung ◽  
Lymphocyte Ratio ◽  
Caucasian Patients ◽  
Egfr Mutated

Purpose Lung cancer is one of the leading causes of cancer-related death worldwide and, although targeted therapy with tyrosine kinase inhibitors has dramatically improved the rates of response and survival in advanced EGFR-mutated adenocarcinoma, the overall outcome remains unsatisfactory. Therefore, new prognostic factors, preferably simple, inexpensive, and easy to reproduce on a large scale, are needed. We performed a retrospective analysis of our database including 63 western Caucasian patients with advanced EGFR-mutated lung adenocarcinoma and receiving gefitinib, erlotinib, or afatinib as first- or second-line therapy. Several studies demonstrated a strong link between elevated neutrophil-to-lymphocyte ratio (NLR) and poor prognosis both in early and advanced stages of non-small-cell lung cancer (NSCLC). Methods From January 2011 to December 2015, 63 consecutive elegible patients with advanced EGFR-mutated NSCLC were included in this analysis from 5 institutions. The NLR was derived from the absolute neutrophil and the absolute lymphocyte counts of a full blood count and the cutoff value was determined according to the mean NLR level. Results Despite the small sample analyzed, we found that NLR has a prognostic role for progression-free survival (PFS) and overall survival (OS), reaching a statistically significant difference with a better PFS and OS in the lower NLR group. Conclusions Pretreatment NLR seems to represent a reliable, simple, and easy to reproduce laboratory tool to predict outcome and response to cancer therapies in this setting of Western Caucasian patients with EGFR-mutated NSCLC.

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