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Precision Oncology in Non-small Cell Lung Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 20166

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Special Issue Editors

Prof. Dr. Alexander Schramm

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Guest Editor

Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Interests: lung cancer; immuno-oncology; targeted therapies; cancer progression; primary and secondary resistance; high-throughput analyses and validation

Dr. Marcel Wiesweg

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Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany

Special Issue Information

Dear Colleagues,

Precision oncology is becoming ever more important in the diagnosis and treatment of lung cancer. In non-small cell lung cancer (NSCLC), alterations in driving oncogenes, including EGFR and ALK, have been successfully introduced as targets for molecularly guided therapies and have become the standard of care. Targeting of alterations occurring in a small fraction of patients, such as ROS1 rearrangements and MET amplification, is also now under evaluation in late-phase clinical trials. However, all of these treatment schedules have in common that tumors evolve evasion strategies to finally develop resistance to all of the agents currently in use. This Special Issue will be dedicated to summarizing the state-of-the-art in precision treatment of NSCLC and will focus on molecular mechanisms of resistance to targeted therapies, strategies to overcome resistance, and monitoring of disease progression and relapse under therapy (e.g., by ctDNA/cfDNA). Authors are encouraged to submit original research manuscripts, but can also provide suggestions for review articles.

Prof. Dr. Alexander Schramm
Dr. Marcel Wiesweg
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

non-small cell lung cancer (NSCLC)
targeted therapy
mechanisms of resistance
EGFR
ALK
oncogenes
ctDNA/cfDNA

Published Papers (5 papers)

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Research

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19 pages, 6955 KiB

Open AccessArticle

Disruption of Cytosolic Folate Integrity Aggravates Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors and Modulates Metastatic Properties in Non-Small-Cell Lung Cancer Cells

by Po-Wen Shen, Chun-Te Ho, Shih-Hsin Hsiao, Yu-Ting Chou, Yi-Cheng Chang and Jun-Jen Liu

Int. J. Mol. Sci. 2021, 22(16), 8838; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168838 - 17 Aug 2021

Cited by 1 | Viewed by 1979

Abstract

Patients with advanced-stage non-small-cell lung cancer (NSCLC) are susceptible to malnutrition and develop folate deficiency (FD). We previously found that folate deprivation induces drug resistance in hepatocellular carcinoma; here, we assessed whether disrupted cytoplasmic folate metabolism could mimic FD-induced metastasis and affect the sensitivity of NSCLC cells to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We examined whether cytosolic folate metabolism in NSCLC cells was disrupted by FD or the folate metabolism blocker pemetrexed for 1–4 weeks. Our results revealed an increase in NF-κB overexpression–mediated epithelial-mesenchymal transition biomarkers: N-cadherin, vimentin, matrix metalloproteinases (MMPs), SOX9, and SLUG. This finding suggests that the disruption of folate metabolism can drastically enhance the metastatic properties of NSCLC cells. Cytosolic FD also affected EGFR-TKI cytotoxicity toward NSCLC cells. Because SLUG and N-cadherin are resistance effectors against gefitinib, the effects of SLUG knockdown in folate antagonist–treated CL1-0 cells were evaluated. SLUG knockdown prevented SLUG/NF-κB/SOX9-mediated invasiveness and erlotinib resistance acquisition and significantly reduced pemetrexed-induced gelatinase activity and MMP gene expression. To summarize, our data reveal two unprecedented adverse effects of folate metabolism disruption in NSCLC cells. Thus, the folic acid status of patients with NSCLC under treatment can considerably influence their prognosis. Full article

(This article belongs to the Special Issue Precision Oncology in Non-small Cell Lung Cancer)

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Review

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13 pages, 1454 KiB

Open AccessReview

The Challenge and Opportunity of NTRK Inhibitors in Non-Small Cell Lung Cancer

by Haixia Qin and Manish R. Patel

Int. J. Mol. Sci. 2022, 23(6), 2916; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23062916 - 08 Mar 2022

Cited by 10 | Viewed by 2858

Abstract

With the development of targeted therapy, non-small cell lung cancer (NSCLC) patients could have more treatment choices if target mutation presents. The neurotrophic tropomyosin receptor kinase (NTRK) has a low prevalence in NSCLC, roughly around 0.5%. FDA had approved two first generation NTRK inhibitors, larotrectinib and entrectinib. Both medications have excellent CNS penetration. This manuscript will review available data on targeting NTRK fusions in NSCLC and mechanisms of drug resistance. Full article

(This article belongs to the Special Issue Precision Oncology in Non-small Cell Lung Cancer)

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20 pages, 1753 KiB

Open AccessReview

Molecular Mechanisms of Chemoresistance Induced by Cisplatin in NSCLC Cancer Therapy

by Jolanta Kryczka, Jakub Kryczka, Karolina H. Czarnecka-Chrebelska and Ewa Brzeziańska-Lasota

Int. J. Mol. Sci. 2021, 22(16), 8885; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168885 - 18 Aug 2021

Cited by 62 | Viewed by 5839

Abstract

Cancer cells utilise several mechanisms to increase their survival and progression as well as their resistance to anticancer therapy: deregulation of growth regulatory pathways by acquiring grow factor independence, immune system suppression, reducing the expression of antigens activating T lymphocyte cells (mimicry), induction of anti-apoptotic signals to counter the action of drugs, activation of several DNA repair mechanisms and driving the active efflux of drugs from the cell cytoplasm, and epigenetic regulation by microRNAs (miRNAs). Because it is commonly diagnosed late, lung cancer remains a major malignancy with a low five-year survival rate; when diagnosed, the cancer is often highly advanced, and the cancer cells may have acquired drug resistance. This review summarises the main mechanisms involved in cisplatin resistance and interactions between cisplatin-resistant cancer cells and the tumour microenvironment. It also analyses changes in the gene expression profile of cisplatin sensitive vs. cisplatin-resistant non-small cell lung cancer (NSCLC) cellular model using the GSE108214 Gene Expression Omnibus database. It describes a protein-protein interaction network that indicates highly dysregulated TP53, MDM2, and CDKN1A genes as they encode the top networking proteins that may be involved in cisplatin tolerance, these all being upregulated in cisplatin-resistant cells. Furthermore, it illustrates the multifactorial nature of cisplatin resistance by examining the diversity of dysregulated pathways present in cisplatin-resistant NSCLC cells based on KEGG pathway analysis. Full article

(This article belongs to the Special Issue Precision Oncology in Non-small Cell Lung Cancer)

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13 pages, 2417 KiB

Open AccessReview

Protein Kinase C as a Therapeutic Target in Non-Small Cell Lung Cancer

by Mohammad Mojtaba Sadeghi, Mohamed F. Salama and Yusuf A. Hannun

Int. J. Mol. Sci. 2021, 22(11), 5527; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115527 - 24 May 2021

Cited by 15 | Viewed by 3954

Abstract

Driver-directed therapeutics have revolutionized cancer treatment, presenting similar or better efficacy compared to traditional chemotherapy and substantially improving quality of life. Despite significant advances, targeted therapy is greatly limited by resistance acquisition, which emerges in nearly all patients receiving treatment. As a result, identifying the molecular modulators of resistance is of great interest. Recent work has implicated protein kinase C (PKC) isozymes as mediators of drug resistance in non-small cell lung cancer (NSCLC). Importantly, previous findings on PKC have implicated this family of enzymes in both tumor-promotive and tumor-suppressive biology in various tissues. Here, we review the biological role of PKC isozymes in NSCLC through extensive analysis of cell-line-based studies to better understand the rationale for PKC inhibition. PKC isoforms α, ε, η, ι, ζ upregulation has been reported in lung cancer, and overexpression correlates with worse prognosis in NSCLC patients. Most importantly, PKC isozymes have been established as mediators of resistance to tyrosine kinase inhibitors in NSCLC. Unfortunately, however, PKC-directed therapeutics have yielded unsatisfactory results, likely due to a lack of specific evaluation for PKC. To achieve satisfactory results in clinical trials, predictive biomarkers of PKC activity must be established and screened for prior to patient enrollment. Furthermore, tandem inhibition of PKC and molecular drivers may be a potential therapeutic strategy to prevent the emergence of resistance in NSCLC. Full article

(This article belongs to the Special Issue Precision Oncology in Non-small Cell Lung Cancer)

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17 pages, 1109 KiB

Open AccessReview

If Virchow and Ehrlich Had Dreamt Together: What the Future Holds for KRAS-Mutant Lung Cancer

by Jens Köhler and Pasi A. Jänne

Int. J. Mol. Sci. 2021, 22(6), 3025; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063025 - 16 Mar 2021

Cited by 6 | Viewed by 4162

Abstract

Non-small-cell lung cancer (NSCLC) with Kirsten rat sarcoma (KRAS) mutations has notoriously challenged oncologists and researchers for three notable reasons: (1) the historical assumption that KRAS is “undruggable”, (2) the disease heterogeneity and (3) the shaping of the tumor microenvironment by KRAS downstream effector functions. Better insights into KRAS structural biochemistry allowed researchers to develop direct KRAS(G12C) inhibitors, which have shown early signs of clinical activity in NSCLC patients and have recently led to an FDA breakthrough designation for AMG-510. Following the approval of immune checkpoint inhibitors for PDL1-positive NSCLC, this could fuel yet another major paradigm shift in the treatment of advanced lung cancer. Here, we review advances in our understanding of the biology of direct KRAS inhibition and project future opportunities and challenges of dual KRAS and immune checkpoint inhibition. This strategy is supported by preclinical models which show that KRAS(G12C) inhibitors can turn some immunologically “cold” tumors into “hot” ones and therefore could benefit patients whose tumors harbor subtype-defining STK11/LKB1 co-mutations. Forty years after the discovery of KRAS as a transforming oncogene, we are on the verge of approval of the first KRAS-targeted drug combinations, thus therapeutically unifying Paul Ehrlich’s century-old “magic bullet” vision with Rudolf Virchow’s cancer inflammation theory. Full article

(This article belongs to the Special Issue Precision Oncology in Non-small Cell Lung Cancer)

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