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Cancers
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Lung Cancer—Molecular Insights and Targeted Therapies (Volume II)
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Lung Cancer—Molecular Insights and Targeted Therapies (Volume II)

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: 30 June 2025 | Viewed by 12278

Special Issue Editor

Dr. Sonia Molina-Pinelo

E-Mail Website
Guest Editor
Institute of Biomedicine of Seville (IBIS), HUVR, CSIC, Universidad de Sevilla, 41013 Sevilla, Spain
Interests: lung cancer; biomarkers; genetics; diagnosis; prognosis; targeted therapies; immunotherapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the second edition of the Special Issue Lung Cancer—Molecular Insights and Targeted Therapies https://www.mdpi.com/journal/cancers/special_issues/LCMITT.

Lung cancer is the leading cause of cancer-related death worldwide, with a 5-year survival rate of approximately 18%. Each year, more than 2 million people are diagnosed with lung cancer around the world, and most of them are diagnosed with locally advanced or metastatic disease. Therefore, early diagnosis is one of the key steps to improve and promote precision medicine for this disease. 

Lung cancer management has changed in the last decade. State-of-the-art molecular pathology has allowed the development of more effective therapeutic strategies for this disease. However, there is still a long way to go before precision medicine is available for all, which will require further research into the molecular mechanisms underlying lung cancer and potential new druggable targets based on the molecular background of tumors. The current issue aims to increase our knowledge in order to achieve these goals.

We are pleased to invite both original research and review articles that highlight recent advances in this exciting field of research. We are looking for articles on the discovery of molecular insights and targeted therapies for use in preclinical in vitro and in vivo models and/or articles investigating their role in translation to clinical practice. We also welcome articles that cover other topics with the aim of improving or providing an alternative paradigm of precision medicine in lung cancer.

I look forward to receiving your contributions.

Dr. Sonia Molina-Pinelo
Guest Editor

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 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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). 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

  • lung cancer
  • non-small-cell lung cancer
  • small-cell lung cancer
  • biomarkers
  • oncogene-drive tumors
  • molecular mechanisms
  • targeted therapies
  • immunotherapy
  • precision medicine
  • preclinical models

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Published Papers (6 papers)

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Research

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18 pages, 2931 KiB  
Article
E. coli Biomolecules Increase Glycolysis and Invasive Potential in Lung Adenocarcinoma
by Alexis A. Vega, Parag P. Shah, Eric C. Rouchka, Brian F. Clem, Calista R. Dean, Natassja Woodrum, Preeti Tanwani, Leah J. Siskind and Levi J. Beverly
Cancers 2025, 17(3), 380; https://doi.org/10.3390/cancers17030380 - 24 Jan 2025
Viewed by 959
Abstract
Introduction: Recent studies have discovered that lung cancer subtypes possess distinct microbiome profiles within their tumor microenvironment. Additionally, the tumor-associated microbiome exhibits altered bacterial pathways, suggesting that certain bacterial families are more capable of facilitating tumor progression than others. We hypothesize that there [...] Read more.
Introduction: Recent studies have discovered that lung cancer subtypes possess distinct microbiome profiles within their tumor microenvironment. Additionally, the tumor-associated microbiome exhibits altered bacterial pathways, suggesting that certain bacterial families are more capable of facilitating tumor progression than others. We hypothesize that there exists a crosstalk between lung adenocarcinoma (LUAD) cells and bacterial cells. Methods and Materials: RNA sequencing (RNA-seq) was performed on LUAD cell lines to explore the paracrine signaling effects of bacterial biomolecules. Based on our RNA-seq data, we investigated glycolysis by measuring glucose uptake and lactate production, invasive potential through invasion assays, and epithelial-to-mesenchymal transition (EMT) markers. Since lipopolysaccharides (LPS), abundant on the cell walls of Gram-negative bacteria, can activate toll-like receptor 4 (TLR4), we inhibited TLR4 with C34 to assess its relationship with the observed phenotypic changes. To identify the bacterial biomolecules responsible for these changes, we treated the media with RNAse enzyme, charcoal or dialyzed away molecules larger than 3 kDa. Results and Discussion: RNA-seq revealed 948 genes upregulated in the presence of E. coli biomolecules. Among these, we observed increased expression of Hexokinase II (HKII), JUN proto-oncogene, and Snail Family Transcriptional Repressor 1. We verified the elevation of glycolytic enzymes through Western blot and saw elevation of 2-deoxyglucose uptake and lactate production in LUAD cell lines incubated in E. coli biomolecules. In addition to E. coli elevating glycolysis in LUAD cell lines, E. coli exposure enhanced invasive potential as demonstrated by Boyden chamber assays. Notably, inhibition of TLR4 did not reduce the impact of E. coli biomolecules on glycolysis or the invasive potential of LUAD. Modulating the E. coli-supplemented media with RNAse enzyme or dextran-coated charcoal or using a spin column to remove biomolecules smaller than 3 kDa resulted in changes in HKII and Claudin protein expression. These findings suggest a direct relationship between E. coli and LUAD, wherein several cancer hallmarks are upregulated. Future studies should further investigate these bacterial biomolecules and their role in the tumor microenvironment to fully understand the impact of microbial shifts on cancer progression. Full article
(This article belongs to the Special Issue Lung Cancer—Molecular Insights and Targeted Therapies (Volume II))
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13 pages, 7082 KiB  
Article
XPC Protects against Carcinogen-Induced Histologic Progression to Lung Squamous Cell Carcinoma by Reduced Basal Epithelial Cell Proliferation
by Catherine R. Sears, Huaxin Zhou, Emily Hulsey, Bea A. Aidoo, George E. Sandusky and Nawar Al Nasrallah
Cancers 2024, 16(8), 1495; https://doi.org/10.3390/cancers16081495 - 13 Apr 2024
Cited by 1 | Viewed by 1648
Abstract
Lung squamous cell carcinoma (LUSC) is the second leading cause of lung cancer. Although characterized by high DNA mutational burdens and genomic complexity, the role of DNA repair in LUSC development is poorly understood. We sought to better understand the role of the [...] Read more.
Lung squamous cell carcinoma (LUSC) is the second leading cause of lung cancer. Although characterized by high DNA mutational burdens and genomic complexity, the role of DNA repair in LUSC development is poorly understood. We sought to better understand the role of the DNA repair protein Xeroderma Pigmentosum Group C (XPC) in LUSC development. XPC knock-out (KO), heterozygous, and wild-type (WT) mice were exposed topically to N-nitroso-tris-chloroethylurea (NTCU), and lungs were evaluated for histology and pre-malignant progression in a blinded fashion at various time-points from 8–24 weeks. High-grade dysplasia and LUSC were increased in XPC KO compared with XPC WT NTCU mice (56% vs. 34%), associated with a higher mean LUSC lung involvement (p < 0.05). N-acetylcysteine pre-treatment decreased bronchoalveolar inflammation but did not prevent LUSC development. Proliferation, measured as %Ki67+ cells, increased with NTCU treatment, in high-grade dysplasia and LUSC, and in XPC deficiency (p < 0.01, ANOVA). Finally, pre-LUSC dysplasia developed earlier and progressed to higher histologic classification sooner in XPC KO compared with WT mice. Overall, this supports the protective role of XPC in squamous dysplasia progression to LUSC. Mouse models of early LUSC development are limited; this may provide a valuable model to study mechanisms of LUSC development and progression. Full article
(This article belongs to the Special Issue Lung Cancer—Molecular Insights and Targeted Therapies (Volume II))
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24 pages, 9592 KiB  
Article
Induction of Multiple Alternative Mitogenic Signaling Pathways Accompanies the Emergence of Drug-Tolerant Cancer Cells
by Frank V. Celeste and Scott Powers
Cancers 2024, 16(5), 1001; https://doi.org/10.3390/cancers16051001 - 29 Feb 2024
Cited by 2 | Viewed by 2082
Abstract
Drug resistance can evolve from a subpopulation of cancer cells that initially survive drug treatment and then gradually form a pool of drug-tolerant cells. Several studies have pinpointed the activation of a specific bypass pathway that appears to provide the critical therapeutic target [...] Read more.
Drug resistance can evolve from a subpopulation of cancer cells that initially survive drug treatment and then gradually form a pool of drug-tolerant cells. Several studies have pinpointed the activation of a specific bypass pathway that appears to provide the critical therapeutic target for preventing drug tolerance. Here, we take a systems-biology approach, using proteomics and genomics to examine the development of drug tolerance to EGFR inhibitors in EGFR-mutant lung adenocarcinoma cells and BRAF inhibitors in BRAF-mutant melanoma cells. We found that there are numerous alternative mitogenic pathways that become activated in both cases, including YAP, STAT3, IGFR1, and phospholipase C (PLC)/protein kinase C (PKC) pathways. Our results suggest that an effective therapeutic strategy to prevent drug tolerance will need to take multiple alternative mitogenic pathways into account rather than focusing on one specific pathway. Full article
(This article belongs to the Special Issue Lung Cancer—Molecular Insights and Targeted Therapies (Volume II))
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14 pages, 4735 KiB  
Article
Combinational Pulsing of TAAs Enforces Dendritic Cell-Based Immunotherapy through T-Cell Proliferation and Interferon-γ Secretion in LLC1 Mouse Model
by Jae-Ung Lee, Sang-Heon Kim, Sung-Hoon Lee, Min-Jae Ji, Jeong-Ah Jin, Hyung-Joon So, Myoung-Lim Song, Hong-Ki Lee and Tae-Wook Kang
Cancers 2024, 16(2), 409; https://doi.org/10.3390/cancers16020409 - 18 Jan 2024
Cited by 2 | Viewed by 1822
Abstract
NSCLC, the most common type of lung cancer, is often diagnosed late due to minimal early symptoms. Its high risk of recurrence or metastasis post-chemotherapy makes DC-based immunotherapy a promising strategy, offering targeted cancer destruction, low side effects, memory formation, and overcoming the [...] Read more.
NSCLC, the most common type of lung cancer, is often diagnosed late due to minimal early symptoms. Its high risk of recurrence or metastasis post-chemotherapy makes DC-based immunotherapy a promising strategy, offering targeted cancer destruction, low side effects, memory formation, and overcoming the immune evasive ability of cancers. However, the limited response to DCs pulsed with single antigens remains a significant challenge. To overcome this, we enhanced DC antigen presentation by pulsing with TAAs. Our study focused on enhancing DC-mediated immune response specificity and intensity by combinatorial pulsing of TAAs, selected for their prevalence in NSCLC. We selected four types of TAAs expressed in NSCLC and pulsed DCs with the optimal combination. Next, we administered TAAs-pulsed DCs into the LLC1 mouse model to evaluate their anti-tumor efficacy. Our results showed that TAAs-pulsed DCs significantly reduced tumor size and promoted apoptosis in tumor tissue. Moreover, TAAs-pulsed DCs significantly increased total T cells in the spleen compared to the unpulsed DCs. Additionally, in vitro stimulation of splenocytes from the TAAs-pulsed DCs showed notable T-cell proliferation and increased IFN-γ secretion. Our findings demonstrate the potential of multiple TAA pulsing to enhance the antigen-presenting capacity of DCs, thereby strengthening the immune response against tumors. Full article
(This article belongs to the Special Issue Lung Cancer—Molecular Insights and Targeted Therapies (Volume II))
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11 pages, 1097 KiB  
Article
Fluorometric Quantification of Total Cell-Free DNA as a Prognostic Biomarker in Non-Small-Cell Lung Cancer Patients Treated with Immune Checkpoint Blockade
by Javier Oliver, Juan Luis Onieva, María Garrido-Barros, Manuel Cobo-Dols, Beatriz Martínez-Gálvez, Ana Isabel García-Pelícano, Jaime Dubbelman, José Carlos Benítez, Juan Zafra Martín, Alejandra Cantero, Elisabeth Pérez-Ruiz, Antonio Rueda-Domínguez and Isabel Barragán
Cancers 2023, 15(13), 3357; https://doi.org/10.3390/cancers15133357 - 26 Jun 2023
Cited by 4 | Viewed by 2171
Abstract
The present study aimed to investigate the potential of basal cell-free fluorometric DNA (cfDNA) quantification as a prognostic biomarker in advanced non-small cell lung cancer (NSCLC) patients treated with an Immune Checkpoint Blockade (ICB). A discovery and validation cohort of 61 and 31 [...] Read more.
The present study aimed to investigate the potential of basal cell-free fluorometric DNA (cfDNA) quantification as a prognostic biomarker in advanced non-small cell lung cancer (NSCLC) patients treated with an Immune Checkpoint Blockade (ICB). A discovery and validation cohort of 61 and 31 advanced lung cancer patients treated with ICB were included in this study. Quantification of cfDNA concentration was performed before the start of the treatment and patients were followed up for a median of 34 (30–40) months. The prognostic predicted value of cfDNA was evaluated based on ROC, and Cox regression was conducted via univariate and multivariate analyses to estimate the hazard ratio. We observed that a cfDNA cut-off of 0.55 ng/µL before the ICB determines the overall survival of patients with a log rank p-value of 3.3 × 10−4. That represents median survivals of 3.8 vs. 17.5 months. Similar results were obtained in the validation cohort being the log rank p-value 3.8 × 10−2 with median survivals of 5.9 vs. 24.3. The univariate and multivariate analysis revealed that the cut-off of 0.55 ng/µL before ICB treatment was an independent predictive factor and was significantly associated with a better survival outcome. High cfDNA concentrations identify patients with advanced NSCLC who do not benefit from the ICB. The determination of cfDNA is a simple test that could select a group of patients in whom new therapeutic strategies are needed. Full article
(This article belongs to the Special Issue Lung Cancer—Molecular Insights and Targeted Therapies (Volume II))
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Review

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29 pages, 5058 KiB  
Review
Non-Small-Cell Lung Cancers (NSCLCs) Harboring RET Gene Fusion, from Their Discovery to the Advent of New Selective Potent RET Inhibitors: “Shadows and Fogs”
by Gianluca Spitaleri, Pamela Trillo Aliaga, Ilaria Attili, Ester Del Signore, Carla Corvaja, Gloria Pellizzari, Jalissa Katrini, Antonio Passaro and Filippo de Marinis
Cancers 2024, 16(16), 2877; https://doi.org/10.3390/cancers16162877 - 19 Aug 2024
Cited by 1 | Viewed by 2503
Abstract
RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1–2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading [...] Read more.
RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1–2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading to the brain. Chemotherapy and immunotherapy have a low impact on the prognosis of these patients. Multitargeted RET inhibitors have shown modest activity jeopardized by high toxicity. New potent and selective RET inhibitors (RET-Is) (pralsetinib and selpercatinib) have achieved a higher efficacy minimizing the known toxicities of the multitargeted agents. This review will describe the sensitivity of immune-checkpoint inhibitors (ICIs) in RET fusion + NSCLC patients, as well their experiences with the ‘old’ multi-targeted RET inhibitors. This review will focus on the advent of new potent and selective RET-Is. We will describe their efficacy as well as the main mechanisms of resistance to them. We will further proceed to deal with the new drugs and strategies proposed to overcome the resistance to RET-Is. In the last section, we will also focus on the safety profile of RET-Is, dealing with the main toxicities as well as the rare but severe adverse events. Full article
(This article belongs to the Special Issue Lung Cancer—Molecular Insights and Targeted Therapies (Volume II))
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