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New Molecular Targets in 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 (31 July 2022) | Viewed by 25139

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Special Issue Editors

Prof. Dr. Federico Cappuzzo

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Guest Editor

Department of Oncology-Hematology, AUSL della Romagna, Ravenna, Italy
Interests: lung cancer; molecular oncology; targeted therapy; immunotherapy
Special Issues, Collections and Topics in MDPI journals

Dr. Serena Ceddia

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Guest Editor

Medical Oncology Unit, University Sapienza, Rome, Italy
Interests: lung cancer; molecular oncology; targeted therapy; immunotherapy

Dr. Lorenza Landi

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Guest Editor

Medical Oncology Unit, National Cancer Institute Regina Elena, Rome, Italy
Interests: lung cancer; molecular oncology; targeted therapy; immunotherapy

Special Issue Information

Dear Colleagues,

For decades oncologists have been convinced that advanced non-small-cell-lung cancer (NSCLC) was a unique disease with an invariable rapid progression and with platinum-based chemotherapy as the only available option for metastatic patients with acceptable performance status. During the past few years, the better knowledge of molecular mechanisms underlying this lethal disease moved researchers to leave this nihilistic attitude in favor of a positive perspective. This is the case of EGFR mutated or ALK-, ROS1- or RET- rearranged NSCLCs, where targeted agents have changed the natural history of disease. The goal of personalized medicine is to assure the right treatment to the right patient and on these perspectives a growing number of other potential druggable targets is rapidly emerging. Unfortunately, even with the most appropriate treatment, patients did not obtain a definitive cure and they became refractory to targets agents due to the emergence of acquired resistance. This Special Issue focuses on current research findings related to molecular mechanisms guiding lung tumor biology, response to therapy and acquired resistance. We invite authors to contribute with either original researches or review articles.

Prof. Dr. Federico Cappuzzo
Dr. Serena Ceddia
Dr. Lorenza Landi
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.

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Keywords

lung cancer
targeted therapy
oncogene addiction
acquired resistance
precision medicine

Published Papers (9 papers)

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Research

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28 pages, 8150 KiB

Open AccessArticle

Unveiling Novel ERCC1–XPF Complex Inhibitors: Bridging the Gap from In Silico Exploration to Experimental Design

by Rita Manguinhas, Patrícia A. Serra, Rita B. Soares, Rafael Rosell, Nuno Gil, Nuno G. Oliveira and Rita C. Guedes

Int. J. Mol. Sci. 2024, 25(2), 1246; https://doi.org/10.3390/ijms25021246 - 19 Jan 2024

Cited by 2 | Viewed by 722

Abstract

Modifications in DNA repair pathways are recognized as prognostic markers and potential therapeutic targets in various cancers, including non-small cell lung cancer (NSCLC). Overexpression of ERCC1 correlates with poorer prognosis and response to platinum-based chemotherapy. As a result, there is a pressing need to discover new inhibitors of the ERCC1–XPF complex that can potentiate the efficacy of cisplatin in NSCLC. In this study, we developed a structure-based virtual screening strategy targeting the inhibition of ERCC1 and XPF interaction. Analysis of crystal structures and a library of small molecules known to act against the complex highlighted the pivotal role of Phe293 (ERCC1) in maintaining complex stability. This residue was chosen as the primary binding site for virtual screening. Using an optimized docking protocol, we screened compounds from various databases, ultimately identifying more than one hundred potential inhibitors. Their capability to amplify cisplatin-induced cytotoxicity was assessed in NSCLC H1299 cells, which exhibited the highest ERCC1 expression of all the cell lines tested. Of these, 22 compounds emerged as promising enhancers of cisplatin efficacy. Our results underscore the value of pinpointing crucial molecular characteristics in the pursuit of novel modulators of the ERCC1–XPF interaction, which could be combined with cisplatin to treat NSCLC more effectively. Full article

(This article belongs to the Special Issue New Molecular Targets in Lung Cancer)

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16 pages, 7231 KiB

Open AccessArticle

NKp44-Derived Peptide Used in Combination Stimulates Antineoplastic Efficacy of Targeted Therapeutic Drugs

by Muhammed Iraqi, Priyanka Bolel, Rhitajit Sarkar, Baisali Bhattacharya, Muhammad Abu Ahmad, Avishay Edri, Laila C. Roisman, Moshe Elkabets, Walid Shalata, Nir Peled and Angel Porgador

Int. J. Mol. Sci. 2022, 23(22), 14054; https://doi.org/10.3390/ijms232214054 - 14 Nov 2022

Cited by 1 | Viewed by 1429

Abstract

Lung cancer cells in the tumor microenvironment facilitate immune evasion that leads to failure of conventional chemotherapies, despite provisionally decided on the genetic diagnosis of patients in a clinical setup. The current study follows three lung cancer patients who underwent “personalized” chemotherapeutic intervention. Patient-derived xenografts (PDXs) were subjected to tumor microarray and treatment screening with chemotherapies, either individually or in combination with the peptide R11-NLS-pep8; this peptide targets both membrane-associated and nuclear PCNA. Ex vivo, employing PDX-derived explants, it was found that combination with R11-NLS-pep8 stimulated antineoplastic effect of chemotherapies that were, although predicted based on the patient’s genetic mutation, inactive on their own. Furthermore, treatment in vivo of PDX-bearing mice showed an exactly similar trend in the result, corroborating the finding to be translated into clinical setup. Full article

(This article belongs to the Special Issue New Molecular Targets in Lung Cancer)

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13 pages, 1211 KiB

Open AccessArticle

Association between Changes in the Patterns of Antinuclear Autoantibodies during Immune Checkpoint Inhibition Therapy and the Development of Severe Immune Related Adverse Events

by Leticia Alserawan, Geòrgia Anguera, Carlos Zamora Atenza, Jorgina Serra López, Laura Martínez-Martínez, Mariona Riudavets Melià, Ivana Sullivan, Andrés Barba Joaquin, Margarita Majem Tarruella and Silvia Vidal

Int. J. Mol. Sci. 2022, 23(20), 12641; https://doi.org/10.3390/ijms232012641 - 20 Oct 2022

Cited by 6 | Viewed by 1815

Abstract

Immune-related adverse events (irAEs) are unpredictable autoimmune-like toxicities induced by immune checkpoint inhibitors (ICI). irAEs are a consequence of a breakdown in self-tolerance. ICIs can induce autoantibody formation, and the presence of antinuclear autoantibodies (ANAs) has been reported in patients who developed irAEs. Our goal was to compare ANA patterns by indirect immunofluorescence at different timepoints before (baseline) and after the initiation of ICI treatment and to analyze the role of ANA pattern changes as predictors of irAEs. This is a 2-year-follow-up prospective study of 152 consecutive patients with solid tumors treated with anti-PD-(L)1 blockade agents. They were included from September 2018 until March 2020 in the Hospital de la Santa Creu I Sant Pau (Barcelona, Spain). We grouped patients into three groups: ANA de novo (patients who showed new ANA patterns at any time after ICI initiation), ANA (ANA positive at baseline without changes in the ANA patterns after initiation of treatment) and non-ANA (ANA negative at baseline and after ICI initiation). We did not find any association between the appearance of ANAs and irAE rates or the number and types of irAEs. However, patients in the ANA de novo group showed higher severe irAE rates (grade ≥ 3) than the other groups. Additionally, in most of the patients with severe irAEs (83.3%), changes in ANA patterns preceded irAE onset. In conclusion, we found ANA induction during ICI therapies in 22 patients and our results suggest that the appearance of ANAs may predict the severity of the irAE. Full article

(This article belongs to the Special Issue New Molecular Targets in Lung Cancer)

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25 pages, 2828 KiB

Open AccessArticle

Regulation of the Soluble Amyloid Precursor Protein α (sAPPα) Levels by Acetylcholinesterase and Brain-Derived Neurotrophic Factor in Lung Cancer Cell Media

by Hind Al Khashali, Ravel Ray, Kai-Ling Coleman, Sarah Atali, Ben Haddad, Jadziah Wareham, Jeffrey Guthrie, Deborah Heyl and Hedeel Guy Evans

Int. J. Mol. Sci. 2022, 23(18), 10746; https://doi.org/10.3390/ijms231810746 - 15 Sep 2022

Cited by 8 | Viewed by 1982

Abstract

In comparing two human lung cancer cells, we previously found lower levels of acetylcholinesterase (AChE) and intact amyloid-β40/42 (Aβ), and higher levels of mature brain-derived neurotrophic factor (mBDNF) in the media of H1299 cells as compared to A549 cell media. In this study, we hypothesized that the levels of soluble amyloid precursor protein α (sAPPα) are regulated by AChE and mBDNF in A549 and H1299 cell media. The levels of sAPPα were higher in the media of H1299 cells. Knockdown of AChE led to increased sAPPα and mBDNF levels and correlated with decreased levels of intact Aβ40/42 in A549 cell media. AChE and mBDNF had opposite effects on the levels of Aβ and sAPPα and were found to operate through a mechanism involving α-secretase activity. Treatment with AChE decreased sAPPα levels and simultaneously increased the levels of intact Aβ40/42 suggesting a role of the protein in shifting APP processing away from the non-amyloidogenic pathway and toward the amyloidogenic pathway, whereas treatment with mBDNF led to opposite effects on those levels. We also show that the levels of sAPPα are regulated by protein kinase C (PKC), extracellular signal-regulated kinase (ERK)1/2, phosphoinositide 3 Kinase (PI3K), but not by protein kinase A (PKA). Full article

(This article belongs to the Special Issue New Molecular Targets in Lung Cancer)

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21 pages, 58357 KiB

Open AccessArticle

Targeting the ERβ/HER Oncogenic Network in KRAS Mutant Lung Cancer Modulates the Tumor Microenvironment and Is Synergistic with Sequential Immunotherapy

by Abdulaziz A. Almotlak, Mariya Farooqui, Adam C. Soloff, Jill M. Siegfried and Laura P. Stabile

Int. J. Mol. Sci. 2022, 23(1), 81; https://doi.org/10.3390/ijms23010081 - 22 Dec 2021

Cited by 6 | Viewed by 2472

Abstract

High ERβ/HER oncogenic signaling defines lung tumors with an aggressive biology. We previously showed that combining the anti-estrogen fulvestrant with the pan-HER inhibitor dacomitinib reduced ER/HER crosstalk and produced synergistic anti-tumor effects in immunocompromised lung cancer models, including KRAS mutant adenocarcinoma. How this combination affects the tumor microenvironment (TME) is not known. We evaluated the effects of fulvestrant and dacomitinib on murine bone marrow-derived macrophages (BMDMs) and CD8+ T cells, and tested the efficacy of the combination in vivo, using the KRAS mutant syngeneic lung adenocarcinoma model, FVBW-17. While this combination synergistically inhibited proliferation of FVBW-17 cells, it had unwanted effects on immune cells, by reducing CD8+ T cell activity and phagocytosis in BMDMs and inducing PD-1. The effects were largely attributed to dacomitinib, which caused downregulation of Src family kinases and Syk in immune cells. In a subcutaneous flank model, the combination induced an inflamed TME with increased myeloid cells and CD8+ T cells and enhanced PD-1 expression in the splenic compartment. Concomitant administration of anti-PD-1 antibody with fulvestrant and dacomitinib was more efficacious than fulvestrant plus dacomitinib alone. Administering anti-PD-1 sequentially after fulvestrant plus dacomitinib was synergistic, with a two-fold greater tumor inhibitory effect compared to concomitant therapy, in both the flank model and in a lung metastasis model. Sequential triple therapy has potential for treating lung cancer that shows limited response to current therapies, such as KRAS mutant lung adenocarcinoma. Full article

(This article belongs to the Special Issue New Molecular Targets in Lung Cancer)

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18 pages, 3414 KiB

Open AccessArticle

EphB4 as a Novel Target for the EGFR-Independent Suppressive Effects of Osimertinib on Cell Cycle Progression in Non-Small Cell Lung Cancer

by Ren Nanamiya, Ryoko Saito-Koyama, Yasuhiro Miki, Chihiro Inoue, Teeranut Asavasupreechar, Jiro Abe, Ikuro Sato and Hironobu Sasano

Int. J. Mol. Sci. 2021, 22(16), 8522; https://doi.org/10.3390/ijms22168522 - 07 Aug 2021

Cited by 8 | Viewed by 2669

Abstract

Osimertinib is the latest generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor used for patients with EGFR-mutated non-small cell lung cancer (NSCLC). We aimed to explore the novel mechanisms of osimertinib by particularly focusing on EGFR-independent effects, which have not been well characterized. We explored the EGFR-independent effects of osimertinib on cell proliferation using NSCLC cell lines, an antibody array analysis, and the association between the action of osimertinib and the ephrin receptor B4 (EphB4). We also studied the clinicopathological significance of EphB4 in 84 lung adenocarcinoma patients. Osimertinib exerted significant inhibitory effects on cell growth and cell cycle progression by promoting the phosphorylation of p53 and p21 and decreasing cyclin D1 expression independently of EGFR. EphB4 was significantly suppressed by osimertinib and promoted cell growth and sensitivity to osimertinib. The EphB4 status in carcinoma cells was positively correlated with tumor size, T factor, and Ki-67 labeling index in all patients and was associated with poor relapse-free survival in EGFR mutation-positive patients. EphB4 is associated with the EGFR-independent suppressive effects of osimertinib on cell cycle and with a poor clinical outcome. Osimertinib can exert significant growth inhibitory effects in EGFR-mutated NSCLC patients with a high EphB4 status. Full article

(This article belongs to the Special Issue New Molecular Targets in Lung Cancer)

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Review

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15 pages, 726 KiB

Open AccessReview

KRAS-Mutant Non-Small-Cell Lung Cancer: From Past Efforts to Future Challenges

by Serena Ceddia, Lorenza Landi and Federico Cappuzzo

Int. J. Mol. Sci. 2022, 23(16), 9391; https://doi.org/10.3390/ijms23169391 - 20 Aug 2022

Cited by 12 | Viewed by 3795

Abstract

KRAS is the most frequently mutated oncogene identified in human cancers. Despite the numerous efforts to develop effective specific inhibitors against KRAS, this molecule has remained “undruggable” for decades. The development of direct KRAS inhibitors, such as sotorasib, the first FDA-approved drug targeting KRAS G12C, or adagrasib, was made possible with the discovery of a small pocket in the binding switch II region of KRAS G12C. However, a new challenge is represented by the necessity to overcome resistance mechanisms to KRAS inhibitors. Another area to be explored is the potential role of co-mutations in the selection of the treatment strategy, particularly in the setting of immune checkpoint inhibitors. The aim of this review was to analyze the state-of-the-art of KRAS mutations in non-small-cell lung cancer by describing the biological structure of KRAS and exploring the clinical relevance of KRAS as a prognostic and predictive biomarker. We reviewed the different treatment approaches, focusing on the novel therapeutic strategies for the treatment of KRAS-mutant lung cancers. Full article

(This article belongs to the Special Issue New Molecular Targets in Lung Cancer)

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22 pages, 1475 KiB

Open AccessReview

Histone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets

by Khuloud Bajbouj, Abeer Al-Ali, Rakhee K. Ramakrishnan, Maha Saber-Ayad and Qutayba Hamid

Int. J. Mol. Sci. 2021, 22(21), 11701; https://doi.org/10.3390/ijms222111701 - 28 Oct 2021

Cited by 46 | Viewed by 6429

Abstract

Lung cancer is the leading cause of cancer mortality in both genders, with non-small cell lung cancer (NSCLC) accounting for about 85% of all lung cancers. At the time of diagnosis, the tumour is usually locally advanced or metastatic, shaping a poor disease outcome. NSCLC includes adenocarcinoma, squamous cell carcinoma, and large cell lung carcinoma. Searching for novel therapeutic targets is mandated due to the modest effect of platinum-based therapy as well as the targeted therapies developed in the last decade. The latter is mainly due to the lack of mutation detection in around half of all NSCLC cases. New therapeutic modalities are also required to enhance the effect of immunotherapy in NSCLC. Identifying the molecular signature of NSCLC subtypes, including genetics and epigenetic variation, is crucial for selecting the appropriate therapy or combination of therapies. Epigenetic dysregulation has a key role in the tumourigenicity, tumour heterogeneity, and tumour resistance to conventional anti-cancer therapy. Epigenomic modulation is a potential therapeutic strategy in NSCLC that was suggested a long time ago and recently starting to attract further attention. Histone acetylation and deacetylation are the most frequently studied patterns of epigenetic modification. Several histone deacetylase (HDAC) inhibitors (HDIs), such as vorinostat and panobinostat, have shown promise in preclinical and clinical investigations on NSCLC. However, further research on HDIs in NSCLC is needed to assess their anti-tumour impact. Another modification, histone methylation, is one of the most well recognized patterns of histone modification. It can either promote or inhibit transcription at different gene loci, thus playing a rather complex role in lung cancer. Some histone methylation modifiers have demonstrated altered activities, suggesting their oncogenic or tumour-suppressive roles. In this review, patterns of histone modifications in NSCLC will be discussed, focusing on the molecular mechanisms of epigenetic modifications in tumour progression and metastasis, as well as in developing drug resistance. Then, we will explore the therapeutic targets emerging from studying the NSCLC epigenome, referring to the completed and ongoing clinical trials on those medications. Full article

(This article belongs to the Special Issue New Molecular Targets in Lung Cancer)

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13 pages, 528 KiB

Open AccessReview

Immune Checkpoints Inhibitors and SRS/SBRT Synergy in Metastatic Non-Small-Cell Lung Cancer and Melanoma: A Systematic Review

by María Rodríguez Plá, Diego Dualde Beltrán and Eduardo Ferrer Albiach

Int. J. Mol. Sci. 2021, 22(21), 11621; https://doi.org/10.3390/ijms222111621 - 27 Oct 2021

Cited by 13 | Viewed by 2666

Abstract

Background: Several immunotherapy (IT) agents are FDA approved for treatment of melanoma and non-small-cell lung cancer (NSCLC). The addition of stereotactic radiosurgery (SRS) or stereotactic body radiation therapy (SBRT) to immunotherapy looks promising. A systematic review was conducted to evaluate the possible synergistic effects of immune checkpoints inhibitors (ICIs) and stereotactic radiation therapy in melanoma and NSCLC. Materials and methods: Pubmed databases from January 2010 to December 2020 were reviewed to identify English language studies reporting control of local and abscopal effect of the combination of ICI-SBRT/SRS in metastatic NSCLC and melanoma cancer. The inclusion criteria were followed according to PICO criteria. Results: Thirty-nine articles were included of the 2141 initial results. The reported rates for local control were 16.5–100% and 40–94% in brain and extracerebral metastases, respectively. Distant/abscopal response rates were 1–45% in extracerebral metastases. Abscopal effect could not be evaluated in brain metastases because it was not reported in studies. Treatments were well tolerated with few grade 4 toxicities and no grade 5. Conclusions: The combined treatment of ICI-SBRT/SRS achieves high local control and non-negligible abscopal response in patients with extracerebral metastases, with its benefit in cerebral metastases being more controversial. Clinical trials are needed to better characterize the potential synergism. Full article

(This article belongs to the Special Issue New Molecular Targets in Lung Cancer)

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