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Molecular Alterations in Non-small Cell Lung Cancer: Biology and Therapeutic Implications

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

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 35462

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Prof. Dr. Carlo Genova

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Department of Internal Medicine and Medical Specialties, Università degli Studi di Genova, 16132 Genova, Italy
Interests: lung cancer; immunotherapy; liquid biopsy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the last decade, studies on molecular alterations in non-small cell lung cancer (NSCLC) have improved the knowledge on the biological pathways involved in tumor development, as well as specific information involving tumor growth signals, inhibition of apoptosis, stimulation of neoangiogenesis, and escape from immune system.

Some of the detected alterations in NSCLC have led to the evolution of antineoplastic therapies; notable examples are represented by activating mutations of the epidermal growth factor receptor (EGFR) gene; furthermore, the list of potentially actionable target genes in NSCLC is constantly increasing. In addition, some emerging molecular alterations appear to be associated with differences in terms of response to immune checkpoint inhibitors, and the mechanisms leading to these correlations are under investigation.

Finally, the exploitation of multiple molecular determinants in NSCLC in the clinical setting strongly relies on multigenic testing techniques, with specific regards to next generation sequencing (NGS); to date, research labs and comprehensive cancer centers worldwide have been putting efforts in updating testing technology in order to comply with demanding standards.

This special issue explores the role of oncogenic drivers in terms of tumorigenesis and as potential therapeutic targets, as well as the NGS technologies needed to optimize the molecular characterization of NSCLC.

Prof. Dr. Carlo Genova
Guest Editor

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Keywords

non-small cell lung cancer
target therapy
next generation sequencing
immunotherapy
EGFR
ALK
ROS1
BRAF
MET
RET
NTRK

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Published Papers (9 papers)

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Editorial

Jump to: Research, Review

3 pages, 192 KiB

Open AccessEditorial

The Long Run towards Personalized Therapy in Non-Small-Cell Lung Cancer: Current State and Future Directions

by Carlo Genova

Int. J. Mol. Sci. 2023, 24(9), 8212; https://doi.org/10.3390/ijms24098212 - 4 May 2023

Cited by 2 | Viewed by 1666

Abstract

Non-small-cell lung cancer (NSCLC) is the major cause of cancer-related deaths worldwide, due to its high incidence and mortality [...] Full article

(This article belongs to the Special Issue Molecular Alterations in Non-small Cell Lung Cancer: Biology and Therapeutic Implications)

Research

Jump to: Editorial, Review

16 pages, 27038 KiB

Open AccessArticle

miR-196a Upregulation Contributes to Gefitinib Resistance through Inhibiting GLTP Expression

by Bing-Jie Liu, Fang-Fang Li, Yun-Xia Xie, Chong-Yuan Fan, Wen-Jing Liu, Jian-Ge Qiu and Bing-Hua Jiang

Int. J. Mol. Sci. 2022, 23(3), 1785; https://doi.org/10.3390/ijms23031785 - 4 Feb 2022

Cited by 7 | Viewed by 2485

Abstract

Tyrosine kinase inhibitor (TKI) therapy has greatly improved lung cancer survival in patients with epidermal growth factor receptor (EGFR) mutations. However, the development of TKI-acquired resistance is the major problem to be overcome. In this study, we found that miR-196a expression was greatly induced in gefitinib-resistant lung cancer cells. To understand the role and mechanism of miR-196a in TKI resistance, we found that miR-196a-forced expression alone increased cell resistance to gefitinib treatment in vitro and in vivo by inducing cell proliferation and inhibiting cell apoptosis. We identified the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) bound to the promoter region of miR-196a and induced miR-196a expression at the transcriptional level. NRF2-forced expression also significantly increased expression levels of miR-196a, and was an upstream inducer of miR-196a to mediate gefitinib resistance. We also found that glycolipid transfer protein (GLTP) was a functional direct target of miR-196a, and downregulation of GLTP by miR-196a was responsible for gefitinib resistance. GLTP overexpression alone was sufficient to increase the sensitivity of lung cancer cells to gefitinib treatment. Our studies identified a new role and mechanism of NRF2/miR-196a/GLTP pathway in TKI resistance and lung tumor development, which may be used as a new biomarker (s) for TKI resistance or as a new therapeutic target in the future. Full article

(This article belongs to the Special Issue Molecular Alterations in Non-small Cell Lung Cancer: Biology and Therapeutic Implications)

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16 pages, 5203 KiB

Open AccessArticle

TdIF1-LSD1 Axis Regulates Epithelial—Mesenchymal Transition and Metastasis via Histone Demethylation of E-Cadherin Promoter in Lung Cancer

by Qi Liu, Juan Xiong, Derong Xu, Nan Hao, Yujuan Zhang, Yi Sang, Zhigang Wang, Xiufen Zheng, Jeffrey Min, Hong Diao, Jacques Raphael, Saman Maleki Vareki, James Koropatnick and Weiping Min

Int. J. Mol. Sci. 2022, 23(1), 250; https://doi.org/10.3390/ijms23010250 - 27 Dec 2021

Cited by 8 | Viewed by 3689

Abstract

We have previously found that TdT-interacting factor 1 (TdIF1) is a potential oncogene expressed in non-small cell lung cancer (NSCLC) and is associated with poor prognosis. However, its exact mechanism is still unclear. The lysine-specific demethylase 1 (LSD1) is a crucial mediator of the epithelial–mesenchymal transition (EMT), an important process triggered during cancer metastasis. Here, we confirm that TdIF1 is highly expressed in NSCLC and related to lymph node metastasis through The Cancer Genome Atlas (TCGA) analysis of clinical samples. Silencing TdIF1 can regulate the expression of EMT-related factors and impair the migration and invasion ability of cancer cells in vitro. An analysis of tumor xenografts in nude mice confirmed that silencing TdIF1 inhibits tumor growth. Furthermore, we determined the interaction between TdIF1 and LSD1 using immunoprecipitation. Chromatin immunoprecipitation (ChIP) revealed that TdIF1 was enriched in the E-cadherin promoter region. The knockdown of TdIF1 repressed the enrichment of LSD1 at the E-cadherin promoter region, thereby regulating the level of promoter histone methylation and modulating E-cadherin transcription activity, ultimately leading to changes in EMT factors and cancer cell migration and invasion ability. The LSD1 inhibitor and TdIF1 knockdown combination showed a synergistic effect in inhibiting the growth, migration, and invasion of NSCLC cells. Taken together, this is the first demonstration that TdIF1 regulates E-cadherin transcription by recruiting LSD1 to the promoter region, thereby promoting EMT and tumor metastasis and highlighting the potential of TdIF1 as a therapeutic target for NSCLC. Full article

(This article belongs to the Special Issue Molecular Alterations in Non-small Cell Lung Cancer: Biology and Therapeutic Implications)

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15 pages, 3388 KiB

Open AccessArticle

L-Type Amino Acid Transporter 1 Regulates Cancer Stemness and the Expression of Programmed Cell Death 1 Ligand 1 in Lung Cancer Cells

by Yi-Heng Liu, Yu-Ling Li, Huan-Ting Shen, Peng-Ju Chien, Gwo-Tarng Sheu, Bing-Yen Wang and Wen-Wei Chang

Int. J. Mol. Sci. 2021, 22(20), 10955; https://doi.org/10.3390/ijms222010955 - 11 Oct 2021

Cited by 14 | Viewed by 3140

Abstract

The l-type amino acid transporter 1 (LAT1) is a membranous transporter that transports neutral amino acids for cells and is dysregulated in various types of cancer. Here, we first observed increased LAT1 expression in pemetrexed-resistant non-small cell lung cancer (NSCLC) cells with high cancer stem cell (CSC) activity, and its mRNA expression level was associated with shorter overall survival in the lung adenocarcinoma dataset of the Cancer Genome Atlas database. The inhibition of LAT1 by a small molecule inhibitor, JPH203, or by RNA interference led to a significant reduction in tumorsphere formation and the downregulation of several cancer stemness genes in NSCLC cells through decreased AKT serine/threonine kinase (AKT)/mammalian target of rapamycin (mTOR) activation. The treatment of the cell-permeable leucine derivative promoted AKT/mTOR phosphorylation and reversed the inhibitory effect of JPH203 in the reduction of CSC activity in pemetrexed-resistant lung cancer cells. Furthermore, we observed that LAT1 silencing caused the downregulation of programmed cell death 1 ligand 1 (PD-L1) on lung cancer cells. The PD-L1⁺/LAT1⁺ subpopulation of NSCLC cells displayed great CSC activity with increased expression of several cancer stemness genes. These data suggest that LAT1 inhibitors can serve as anti-CSC agents and could be used in combination with immune checkpoint inhibitors in lung cancer therapy. Full article

(This article belongs to the Special Issue Molecular Alterations in Non-small Cell Lung Cancer: Biology and Therapeutic Implications)

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Review

Jump to: Editorial, Research

28 pages, 2716 KiB

Open AccessReview

Morphologic-Molecular Transformation of Oncogene Addicted Non-Small Cell Lung Cancer

by Fiorella Calabrese, Federica Pezzuto, Francesca Lunardi, Francesco Fortarezza, Sofia-Eleni Tzorakoleftheraki, Maria Vittoria Resi, Mariaenrica Tiné, Giulia Pasello and Paul Hofman

Int. J. Mol. Sci. 2022, 23(8), 4164; https://doi.org/10.3390/ijms23084164 - 9 Apr 2022

Cited by 11 | Viewed by 3691

Abstract

Patients with non-small cell lung cancer, especially adenocarcinomas, harbour at least one oncogenic driver mutation that can potentially be a target for therapy. Treatments of these oncogene-addicted tumours, such as the use of tyrosine kinase inhibitors (TKIs) of mutated epidermal growth factor receptor, have dramatically improved the outcome of patients. However, some patients may acquire resistance to treatment early on after starting a targeted therapy. Transformations to other histotypes—small cell lung carcinoma, large cell neuroendocrine carcinoma, squamous cell carcinoma, and sarcomatoid carcinoma—have been increasingly recognised as important mechanisms of resistance and are increasingly becoming a topic of interest for all specialists involved in the diagnosis, management, and care of these patients. This article, after examining the most used TKI agents and their main biological activities, discusses histological and molecular transformations with an up-to-date review of all previous cases published in the field. Liquid biopsy and future research directions are also briefly discussed to offer the reader a complete and up-to-date overview of the topic. Full article

(This article belongs to the Special Issue Molecular Alterations in Non-small Cell Lung Cancer: Biology and Therapeutic Implications)

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19 pages, 2032 KiB

Open AccessReview

Ferroptosis in Non-Small Cell Lung Cancer: Progression and Therapeutic Potential on It

by Jiayu Zou, Li Wang, Hailin Tang, Xiuxiu Liu, Fu Peng and Cheng Peng

Int. J. Mol. Sci. 2021, 22(24), 13335; https://doi.org/10.3390/ijms222413335 - 11 Dec 2021

Cited by 63 | Viewed by 7905

Abstract

As a main subtype of lung cancer, the current situation of non-small cell lung cancer (NSCLC) remains severe worldwide with a 19% survival rate at 5 years. As the conventional therapy approaches, such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy, gradually develop into therapy resistance, searching for a novel therapeutic strategy for NSCLC is urgent. Ferroptosis, an iron-dependent programmed necrosis, has now been widely considered as a key factor affecting the tumorigenesis and progression in various cancers. Focusing on its effect in NSCLC, in different situations, ferroptosis can be triggered or restrained. When ferroptosis was induced in NSCLC, it was available to inhibit the tumor progression both in vitro and in vivo. The dominating mechanism was due to a regulation of the classic ferroptosis-repressed GSH-dependent GPX4 signaling pathway instead of other fractional regulating signal axes that regulated ferroptosis via impacting on the ROS, cellular iron levels, etc. In terms of the prevention of ferroptosis in NSCLC, an GSH-independent mechanism was also discovered, interestingly exhibiting the same upstream as the GPX4 signaling. In addition, this review summarizes the progression of ferroptosis in NSCLC and elaborates their association and specific mechanisms through bioinformatics analysis with multiple experimental evidence from different cascades. Finally, this review also points out the possibility of ferroptosis working as a novel strategy for therapy resistance in NSCLC, emphasizing its therapeutic potential. Full article

(This article belongs to the Special Issue Molecular Alterations in Non-small Cell Lung Cancer: Biology and Therapeutic Implications)

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17 pages, 1072 KiB

Open AccessReview

Deepening the Knowledge of ROS1 Rearrangements in Non-Small Cell Lung Cancer: Diagnosis, Treatment, Resistance and Concomitant Alterations

by Giorgia Guaitoli, Federica Bertolini, Stefania Bettelli, Samantha Manfredini, Michela Maur, Lucia Trudu, Beatrice Aramini, Valentina Masciale, Giulia Grisendi, Massimo Dominici and Fausto Barbieri

Int. J. Mol. Sci. 2021, 22(23), 12867; https://doi.org/10.3390/ijms222312867 - 28 Nov 2021

Cited by 17 | Viewed by 3982

Abstract

ROS proto-oncogene 1 (ROS1) rearrangements are reported in about 1–2% of non-squamous non-small-cell lung cancer (NSCLC). After efficacy of crizotinib was demonstrated, identification of ROS1 translocations in advanced disease became fundamental to give patients the chance of specific and effective treatment. Different methods are available for detection of rearrangements, and probably the real prevalence of ROS1 rearrangements is higher than that reported in literature, as our capacity to detect gene rearrangements is improving. In particular, with next generation sequencing (NGS) techniques, we are currently able to assess multiple genes simultaneously with increasing sensitivity. This is leading to overcome the “single oncogenic driver” paradigm, and in the very near future, the co-existence of multiple drivers will probably emerge more frequently and represent a therapeutic issue. Since recently, crizotinib has been the only available therapy, but today, many other tyrosine kinase inhibitors (TKI) are emerging and seem promising both in first and subsequent lines of treatment. Indeed, novel inhibitors are also able to overcome resistance mutations to crizotinib, hypothesizing a possible sequential strategy also in ROS1-rearranged disease. In this review, we will focus on ROS1 rearrangements, dealing with diagnostic aspects, new therapeutic options, resistance issues and the coexistence of ROS1 translocations with other molecular alterations. Full article

(This article belongs to the Special Issue Molecular Alterations in Non-small Cell Lung Cancer: Biology and Therapeutic Implications)

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28 pages, 11975 KiB

Open AccessReview

Cell Behavior of Non-Small Cell Lung Cancer Is at EGFR and MicroRNAs Hands

by Sarah Sayed Hassanein, Sherif Abdelaziz Ibrahim and Ahmed Lotfy Abdel-Mawgood

Int. J. Mol. Sci. 2021, 22(22), 12496; https://doi.org/10.3390/ijms222212496 - 19 Nov 2021

Cited by 23 | Viewed by 4670

Abstract

Lung cancer is a complex disease associated with gene mutations, particularly mutations of Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) and epidermal growth factor receptor (EGFR). Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are the two major types of lung cancer. The former includes most lung cancers (85%) and are commonly associated with EGFR mutations. Several EGFR-tyrosine kinase inhibitors (EGFR-TKIs), including erlotinib, gefitinib, and osimertinib, are effective therapeutic agents in EGFR-mutated NSCLC. However, their effectiveness is limited by the development (acquired) or presence of intrinsic drug resistance. MicroRNAs (miRNAs) are key gene regulators that play a profound role in the development and outcomes for NSCLC via their role as oncogenes or oncosuppressors. The regulatory role of miRNA-dependent EGFR crosstalk depends on EGFR signaling pathway, including Rat Sarcoma/Rapidly Accelerated Fibrosarcoma/Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase 1/2 (Ras/Raf/MEK/ERK1/2), Signal Transducer and Activator of Transcription (STAT), Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-kB), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), Janus kinase 1 (JAK1), and growth factor receptor-bound protein 2 (GRB2). Dysregulated expression of miRNAs affects sensitivity to treatment with EGFR-TKIs. Thus, abnormalities in miRNA-dependent EGFR crosstalk can be used as diagnostic and prognostic markers, as well as therapeutic targets in NSCLC. In this review, we present an overview of miRNA-dependent EGFR expression regulation, which modulates the behavior and progression of NSCLC. Full article

(This article belongs to the Special Issue Molecular Alterations in Non-small Cell Lung Cancer: Biology and Therapeutic Implications)

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14 pages, 505 KiB

Open AccessReview

Safety of Surgery after Neoadjuvant Targeted Therapies in Non-Small Cell Lung Cancer: A Narrative Review

by Tomasz Marjanski, Robert Dziedzic, Anna Kowalczyk and Witold Rzyman

Int. J. Mol. Sci. 2021, 22(22), 12244; https://doi.org/10.3390/ijms222212244 - 12 Nov 2021

Cited by 6 | Viewed by 2943

Abstract

New drugs, including immune checkpoint inhibitors and targeted therapy, have changed the prognosis in a subset of patients with advanced lung cancer, and are now actively investigated in a number of trials with neoadjuvant and adjuvant regimens. However, no phase III randomized studies were published yet. The current narrative review proves that targeted therapies are safe in neoadjuvant approach. Unsurprisingly, administration of therapy is related to an acceptable toxicity profile. Severe adverse events’ rate that rarely compromises outcomes of patients with advanced lung cancer is not that commonly accepted in early lung cancer as it may lead to missing the chance of curative surgery. Among those complications, the most important factors that may limit the use of targeted therapies are severe respiratory adverse events precluding the resection occurring after treatment with some anaplastic lymphoma kinase and rarely after epidermal growth factor receptor tyrosine kinase inhibitors. At this point, in the presented literature assessing the feasibility of neoadjuvant therapies with anaplastic lymphoma kinase and epidermal growth factor receptor tyrosine kinase inhibitors, we did not find any unexpected intraoperative events that would be of special interest to a thoracic surgeon. Moreover, the postoperative course was associated with typical rate of complications. Full article

(This article belongs to the Special Issue Molecular Alterations in Non-small Cell Lung Cancer: Biology and Therapeutic Implications)

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