Lung Cancer: Molecular Pathways, Current Therapies and New Targeted Treatments

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

Deadline for manuscript submissions: 30 November 2024 | Viewed by 4560

Special Issue Editors


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Guest Editor
Laboratory of Molecular Cell Biology, Cell Cycle and Proteomics, Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece
Interests: cancer; development of chemical compounds; lung cancer; autophagy; immunotherapy

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Guest Editor
Radiobiology and Radiopathology Unit, Department of Radiotherapy and Oncology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece
Interests: lung cancer; prostate cancer; pancreatic cancer; autophagy; immunotherapy

Special Issue Information

Dear Colleagues,

According to the WHO, lung cancer constitutes the most lethal type of tumor and accounts for a huge number of deaths worldwide. In 2020, lung cancer caused near to 2 million deaths and 2.2 million new cases. The most common types of lung cancer are small-cell lung cancer (SCLC) and the non-small-cell lung cancer (NSCLC).  Many scientific groups are working on lung cancer, producing deeper knowledge about its genetic background and risk factors. Smoking and air pollution have been recognized as two factors heavily augmenting the possibility of lung cancer development. Similarly to several other types of cancer, the traditional approaches of surgery, radiotherapy, and chemotherapy serve as treatment options for lung cancer. However, over the last decade, immunotherapy and target-specific drugs (e.g., Erlotinib, Gelfitinib, and Crizotinib) have been introduced to clinical practice.  Nowadays, it has been proven that the disruption of cellular processes in cancer cells such as glucose metabolism, autophagy, apoptosis, and others can have a big impact on the efficacy of the treatment. Therefore, understanding the molecular mechanisms behind those disruptions could have a great impact on clinical practice by improving our current therapeutic options or by helping the development of new therapeutic approaches. The goal of this Special Issue is to highlight the new scientific achievements related to the molecular pathways that can serve as targets for new treatments or as targets enhancing the efficacy of current treatments.

Dr. Achilleas Mitrakas
Dr. Christos Kakouratos
Guest Editors

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Keywords

  • lung cancer
  • current therapies
  • cancer cell metabolism
  • autophagy
  • NSCLC
  • immunotherapy
  • targeted treatments

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Published Papers (4 papers)

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Research

16 pages, 3849 KiB  
Article
Autophagy Blockage Up-Regulates HLA-Class-I Molecule Expression in Lung Cancer and Enhances Anti-PD-L1 Immunotherapy Efficacy
by Erasmia Xanthopoulou, Ioannis Lamprou, Achilleas G. Mitrakas, Georgios D. Michos, Christos E. Zois, Alexandra Giatromanolaki, Adrian L. Harris and Michael I. Koukourakis
Cancers 2024, 16(19), 3272; https://doi.org/10.3390/cancers16193272 - 26 Sep 2024
Viewed by 636
Abstract
Background/Objectives: Immune checkpoint inhibitors have an established role in non-small cell lung cancer (NSCLC) therapy. The loss of HLA-class-I expression allows cancer cell evasion from immune surveillance, disease progression, and failure of immunotherapy. The restoration of HLA-class-I expression may prove to be a [...] Read more.
Background/Objectives: Immune checkpoint inhibitors have an established role in non-small cell lung cancer (NSCLC) therapy. The loss of HLA-class-I expression allows cancer cell evasion from immune surveillance, disease progression, and failure of immunotherapy. The restoration of HLA-class-I expression may prove to be a game-changer in current immunotherapy strategies. Autophagic activity has been recently postulated to repress HLA-class-I expression in cancer cells. Methods: NSCLC cell lines (A549 and H1299) underwent late-stage (chloroquine and bafilomycin) and early-stage autophagy blockage (ULK1 inhibitors and MAP1LC3A silencing). The HLA-class-I expression was assessed with flow cytometry, a Western blot, and RT-PCR. NSCLC tissues were examined for MAP1LC3A and HLA-class-I expression using double immunohistochemistry. CD8+ T-cell cytotoxicity was examined in cancer cells pre-incubated with chloroquine and anti-PD-L1 monoclonal antibodies (Moabs); Results: A striking increase in HLA-class-I expression following incubation with chloroquine, bafilomycin, and IFNγ was noted in A549 and H1299 cancer cells, respectively. This effect was further confirmed in CD133+ cancer stem cells. HLA-class-I, β2-microglobulin, and TAP1 mRNA levels remained stable. Prolonged exposure to chloroquine further enhanced HLA-class-I expression. Similar results were noted following exposure to a ULK1 and a PIKfyve inhibitor. Permanent silencing of the MAP1LC3A gene resulted in enhanced HLA-class-I expression. In immunohistochemistry experiments, double LC3A+/HLA-class-I expression was seldom. Pre-incubation of H1299 cancer cells with chloroquine and anti-PD-L1 MoAbs increased the mean % of apoptotic/necrotic cells from 2.5% to 18.4%; Conclusions: Autophagy blockers acting either at late or early stages of the autophagic process may restore HLA-class-I-mediated antigen presentation, eventually leading to enhanced immunotherapy efficacy. Full article
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11 pages, 1107 KiB  
Article
Mitochondrial Dynamics in Non-Small Cell Lung Cancer
by Agata Dutkowska, Daria Domańska-Senderowska, Karolina H. Czarnecka-Chrebelska, Ewa Pikus, Aleksandra Zielińska, Laura Biskup, Agata Kołodziejska, Paulina Madura, Maria Możdżan, Urszula Załuska, Edward Zheng, Eliza Adamczyk, Konrad Kędzia, Szymon Wcisło, Marcin Wawrzycki, Ewa Brzeziańska-Lasota, Sławomir Jabłoński, Adam Antczak and Michał Poznański
Cancers 2024, 16(16), 2823; https://doi.org/10.3390/cancers16162823 - 12 Aug 2024
Viewed by 803
Abstract
In lung cancer patients, two complementary abnormalities were found that can cause disruption of the mitochondrial network: increased fusion and impaired fission, manifested by reduced levels of FIS1, a mitochondrial division regulator, and increased expression of MFN1, a mitochondrial fusion mediator. Immunoexpression studies [...] Read more.
In lung cancer patients, two complementary abnormalities were found that can cause disruption of the mitochondrial network: increased fusion and impaired fission, manifested by reduced levels of FIS1, a mitochondrial division regulator, and increased expression of MFN1, a mitochondrial fusion mediator. Immunoexpression studies of MFN1 and FIS1 proteins were performed in serum samples obtained from 47 patients with non-small cell lung cancer (NSCLC) and 21 controls. In the NSCLC patients, the immunoexpression of the MFN1 protein was significantly higher, and the FIS1 protein level was significantly lower than in the control group (p < 0.01; p < 0.001; UMW test). Patients with early, operable lung cancer had significantly lower levels of MFN1 immunoexpression compared to patients with advanced, metastatic lung cancer (p < 0.05; UMW test). This suggests that early stages of the disease are characterized by greater fragmentation of damaged mitochondria and apoptosis. In contrast, lower FIS1 protein levels were associated with a worse prognosis. Increased mitochondrial fusion in the blood of lung cancer patients may suggest an increase in protective and repair mechanisms. This opens up questions about why these mechanisms fail in the context of existing advanced cancer disease and is a starting point for further research into why protective mechanisms fail in lung cancer patients. Full article
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15 pages, 9953 KiB  
Article
Smoking-Mediated miR-301a/IRF1 Axis Controlling Immunotherapy Response in Lung Squamous Cell Carcinoma Revealed by Bioinformatic Analysis
by Alina M. Perevalova, Vladislav V. Kononchuk, Tatiana S. Kalinina, Vadim V. Kozlov, Lyudmila F. Gulyaeva and Vladimir O. Pustylnyak
Cancers 2024, 16(12), 2208; https://doi.org/10.3390/cancers16122208 - 13 Jun 2024
Viewed by 900
Abstract
Smoking is an established risk factor for a variety of malignant tumors, the most well-known of which is lung cancer. Various molecular interactions are known to link tobacco smoke exposure to lung cancer, but new data are still emerging on the effects of [...] Read more.
Smoking is an established risk factor for a variety of malignant tumors, the most well-known of which is lung cancer. Various molecular interactions are known to link tobacco smoke exposure to lung cancer, but new data are still emerging on the effects of smoking on lung cancer development, progression, and tumor response to therapy. In this study, we reveal in further detail the previously established association between smoking and hsa-mir-301a activity in lung squamous cell carcinoma, LUSC. Using different bioinformatic tools, we identified IRF1 as a key smoking-regulated target of hsa-mir-301a in LUSC. We further confirmed this relationship experimentally using clinical LUSC tissue samples and intact lung tissue samples. Thus, increased hsa-mir-301a levels, decreased IRF1 mRNA levels, and their negative correlation were shown in LUSC tumor samples. Additional bioinformatic investigation for potential pathways impacted by such a mechanism demonstrated IRF1’s multifaceted role in controlling the antitumor immune response in LUSC. IRF1 was then shown to affect tumor immune infiltration, the expression of immune checkpoint molecules, and the efficacy of immune checkpoint blockade therapy. As a result, here we suggest a smoking-regulated mir301a/IRF1 molecular axis that could modulate the antitumor immune response and immunotherapy efficacy in LUSC, opening up novel opportunities for future research. Full article
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11 pages, 973 KiB  
Article
Ultra-Hypofractionated Re-Irradiation with Anti-PD-1 Immunotherapy for Locoregionally Recurrent (after Radical Chemo-Radiotherapy) Non-Small Cell Lung Cancer
by Konstantinos Filippatos, Ioannis M. Koukourakis, Stavros Anevlavis, Axiotis Giaktzidis and Michael I. Koukourakis
Cancers 2023, 15(20), 5083; https://doi.org/10.3390/cancers15205083 - 20 Oct 2023
Cited by 1 | Viewed by 1405
Abstract
Large fractions of radiotherapy of 8 Gy (ultra-hypofractionated RT, ultra-hypoRT) promote anti-tumor immune responses that have been clinically substantiated in combination trials with immune checkpoint inhibitors (ICIs). In the current study, we postulated that ultra-hypoRT in combination with ICIs may enhance tumor clearance [...] Read more.
Large fractions of radiotherapy of 8 Gy (ultra-hypofractionated RT, ultra-hypoRT) promote anti-tumor immune responses that have been clinically substantiated in combination trials with immune checkpoint inhibitors (ICIs). In the current study, we postulated that ultra-hypoRT in combination with ICIs may enhance tumor clearance in NSCLC patients with locoregional relapse after radical chemo-RT. Between 2019 and 2021, eleven patients received re-irradiation with one or two fractions of 8 Gy concurrently with anti-PD1 immunotherapy (nivolumab or pembrolizumab). RT-related toxicities were negligible, while immune-related adverse events enforced immunotherapy interruption in 36% of patients. The overall response rate was 81.8%. Tumor reduction between 80 and 100% was noted in 63.5% of patients. Within a median follow-up of 22 months, the locoregional relapse-free rate was 54.5%, while the projected 2-year disease-specific overall survival was 62%. The results were independent of PD-L1 status. The current report provides encouraging evidence that a relatively low biological dose of RT delivered with 8 Gy fractions is feasible and can be safely combined with anti-PD-1 immunotherapy. Despite the low number of patients, the significant tumor regression achieved and the long-lasting locoregional control and overall progression-free intervals provide a basis to pursue immuno-RT trials with U-hypoRT schemes in this group of NSCLC patients of poor prognosis. Full article
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