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Challenges and Future Perspectives in Treatment for 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: 20 July 2025 | Viewed by 8023

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Special Issue Editors

Dr. Ilaria Marrocco

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Guest Editor

Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
Interests: EGFR; lung cancer; tyrosine kinase inhibitors; monoclonal antibodies; drug resistance
Special Issues, Collections and Topics in MDPI journals

Dr. Donatella Romaniello

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Guest Editor

Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy
Interests: cancer biology; stat3; signal transduction; chemoresistance; immunotherapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Lung cancer, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), is the second most common cancer and the leading cause of cancer-related deaths worldwide. The availability of diverse intervention options (surgery, chemotherapy, radiotherapy, targeted therapy, immunotherapy) has improved the survival of patients in recent decades. However, additional insights must be gained in order to improve the outcome of this disease.

For this reason, this Special Issue aims to highlight the most recent scientific advances directed at improving the treatment strategies available for both SCLC and NSCLC.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

Diagnostic, prognostic and predictive biomarkers in lung cancer;
Molecular mutations in lung cancer such as the epidermal growth factor receptor (EGFR) gene, ALK rearrangements and KRAS mutations;
Epidermal growth factor receptor (EFGR)-targeted therapies and drug resistance;
New therapeutic approaches and drug delivery in lung cancer, such as the role of mutation analysis and next-generation sequencing (NGS) in lung cancer diagnosis and treatment.

Research advances in chemotherapy, targeted therapy and immunotherapy are also welcomed.

We look forward to receiving your contributions.

Dr. Ilaria Marrocco
Dr. Donatella Romaniello
Guest Editors

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Keywords

lung cancer
non-small cell lung cancer
small cell lung cancer
chemotherapy
targeted therapy
immunotherapy
drug resistance
drug delivery

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Published Papers (7 papers)

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Research

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17 pages, 1352 KiB

Open AccessArticle

Combined Immune Checkpoint Blockade and Helixor^® Therapy in Oncology: Real-World Tolerability and Subgroup Survival (ESMO GROW)

by Anja Thronicke, Patricia Grabowski, Juliane Roos, Hannah Wüstefeld, Christian Grah, Sophia Johnson and Friedemann Schad

Int. J. Mol. Sci. 2025, 26(8), 3669; https://doi.org/10.3390/ijms26083669 - 12 Apr 2025

Viewed by 344

Abstract

Real-world data (RWD) play a crucial role in identifying key subgroups and assessing multimodal oncology therapies, including integrative and palliative care. Immune checkpoint blockade (ICB) has improved survival, and its combination with complementary therapies like Viscum album L. extracts (VA) may enhance outcomes. This RWD study, based on the Network Oncology registry and ESMO-GROW guidelines, analyzed oncological patients receiving PD-1/PD-L1 inhibitors alone or with Helixor^® VA (HVA) extracts. Primary and secondary objectives were tolerability and overall survival. Statistical analyses included Kaplan–Meier survival curves and Cox regression. Among 405 cancer patients, 344 received ICB alone (CTRL) and 61 received ICB + HVA (COMB). Lung cancer was predominant (78.6%). Adverse event-related discontinuation was lower in COMB (4.9% vs. 6.4%, p = 0.25). In non-small cell lung cancer (NSCLC) patients, the 3-year survival rate was significantly higher in COMB (34.3% vs. 17.2%, p = 0.02). In female NSCLC patients, COMB was significantly associated with a reduced death risk of 91.2% (aHR: 0.088; 95% CI: 0.009–0.783). Our RWD findings show the favorable tolerability of combinatorial ICB + HVA in several tumor entities and underscore its potential to improve survival in NSCLC particularly in female NSCLC patients, warranting further investigation. Full article

(This article belongs to the Special Issue Challenges and Future Perspectives in Treatment for Lung Cancer)

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14 pages, 1303 KiB

Open AccessArticle

Benefit of Consolidation Thoracic Radiotherapy in Extensive-Stage Small-Cell Lung Cancer Patients Treated with Immunotherapy: Data from Slovenian Cohort

by Marina Čakš, Urška Janžič, Tjaša Rutar, Mojca Unk, Ana Demšar, Katja Mohorčič, Nina Turnšek, Erika Matos and Jasna But-Hadžić

Int. J. Mol. Sci. 2025, 26(8), 3631; https://doi.org/10.3390/ijms26083631 - 11 Apr 2025

Viewed by 201

Abstract

Chemoimmunotherapy (CT/IO) with immune checkpoint inhibitors has recently become the standard of care for extensive-stage small cell lung cancer (ES-SCLC). Given the uncertain role of consolidation thoracic radiotherapy (cTRT) in this setting, we conducted a real-world study to evaluate the efficacy and safety of cTRT in ES-SCLC patients receiving first-line CT/IO. We performed a retrospective analysis of ES-SCLC patients treated with first-line CT/IO in Slovenia from December 2019 to June 2024. Patient characteristics, treatment patterns, survival outcomes, and adverse events were analyzed, with subgroup comparisons based on cTRT administration. Among 208 patients (median age: 66 years), median overall survival was 12.1 months (95% CI: 10.6–13.7). cTRT was administered to 46 patients (22.1%), who had fewer metastases. cTRT was associated with improved OS (17.0 vs. 10.8 months; p < 0.001) and was an independent OS predictor (HR = 0.58, p = 0.035). Grade ≥ 3 adverse events were similar (26.1% vs. 21.3%), though pneumonitis occurred more frequently with cTRT (6.5% vs. 0%, p = 0.001). cTRT may improve survival in ES-SCLC patients treated with CT/IO, with no significant increase in toxicity apart from pneumonitis. Further prospective studies are needed. Full article

(This article belongs to the Special Issue Challenges and Future Perspectives in Treatment for Lung Cancer)

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16 pages, 1265 KiB

Open AccessArticle

Prospective Upfront Next-Generation Sequencing for Advanced Non-Small Cell Lung Cancer: Real-World Outcomes from the Ion Chiricuță Oncology Institute

by Alexandra Cristina Preda, Nicolae Todor, Bogdan Cârlan, Adelina-Dadiana Kubelac-Varro, Dana Ioana Iancu, Cristina Mocan, Mariana Bandi Vasilica, Milan-Paul Kubelac, Cătălin Vlad and Tudor Eliade Ciuleanu

Int. J. Mol. Sci. 2025, 26(7), 3403; https://doi.org/10.3390/ijms26073403 - 5 Apr 2025

Viewed by 329

Abstract

Upfront Next-Generation Sequencing (NGS) is increasingly recommended in advanced NSCLC to guide targeted therapy. This prospective single-center study in Romania evaluated routine, upfront NGS in advanced NSCLC at baseline (tissue and/or liquid) and progression (liquid). Baseline FoundationOne NGS (tissue/liquid) was performed in 119 consecutive stage IV NSCLC patients, along with PD-L1 immunohistochemistry (IHC, SP263). Liquid biopsy was repeated at progression. Turnaround time (TAT), the prevalence of actionable targets, and clinical utility were assessed. Patients were predominantly male (68.1%) with a median age of 62 years (range 30–86). Most had ECOG PS 0–1 (79%) and non-squamous histology (67.2%). Never-smokers accounted for 25.2%. The median TAT for the NGS results was 9 days (range 5–21). Overall, 671 genetic alterations were detected in 149 genes. The mean number of distinct mutations per patient dropped from 5.6 at baseline to 4.3 at progression. Tissue samples yielded more alterations (6 per patient) than baseline liquid biopsies (4.6). Squamous tumors had more alterations (7.1 vs. 4.8 in non-squamous), and the number of smokers exceeded that of never-smokers (6 vs. 4.5). TP53 was the most frequent (70.59%). Actionable variants were found in 74.8% of patients, though only 35.3% received personalized therapy, largely due to performance status deterioration, reimbursement, or trial availability barriers. Common targets in non-squamous tumors included EGFR (21%), KRAS G12C (11%), NF1 (11%), and ERBB2 (6%); in squamous tumors, common targets included NF1 (24%), PIK3CA (18%), and ERBB2 (8%). Among smokers, driver mutations were often NF1 (15%), PIK3CA (11%), KRAS G12C (9%), and ERBB2 (8%); never-smokers were dominated by EGFR (45%), NF1 (15%), and KRAS G12C (8%). TMB ≥ 10 mut/Mb was seen in 26.9%; no patients were MSI-H. PD-L1 TPS was <1% in 33% of patients, 1–49% in 20%, ≥50% in 18%, and unknown in 29%. Upfront NGS offers rapid, comprehensive genomic data, guiding tailored therapies and trials in advanced NSCLC. Liquid rebiopsy at progression further refines treatment decisions. Full article

(This article belongs to the Special Issue Challenges and Future Perspectives in Treatment for Lung Cancer)

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20 pages, 6547 KiB

Open AccessArticle

Plasma-Activated Medium Inhibited the Proliferation and Migration of Non-Small Cell Lung Cancer A549 Cells in 3D Culture

by Zhidan Sun, Chenglong Ding, Yuhan Wang, Tingting Lu and Wencheng Song

Int. J. Mol. Sci. 2024, 25(24), 13262; https://doi.org/10.3390/ijms252413262 - 10 Dec 2024

Cited by 1 | Viewed by 1148

Abstract

Lung cancer is the most common type of malignant tumor worldwide. Plasma-activated medium (PAM) is an innovative cancer treatment method that has received considerable scientific attention. The objective of this study is to evaluate the effects of PAM on the anti-tumor characteristics of non-small cell lung cancer (NSCLC) cells in two-dimensional (2D) and three-dimensional (3D) cultures. The effects of PAM treatment on the proliferative and migratory capabilities of A549 cells in 2D and 3D cultures were assessed using MTT, migration, invasion assays, and cell cycle, respectively. The study also investigated the impact of PAM treatment on the changes in the content of intracellular and extracellular reactive species and analyzed protein expression using the Western Blot method. PAM treatment inhibited the viability, migration, and invasion abilities of A549 cells in both 2D and 3D cultures, suppressed the epithelial–mesenchymal transition (EMT) process, and downregulated the expression of the RAS/ERK signaling pathway, which effectively inhibited tumor spheroid formation. Additionally, the effect of PAM on A549 cells was mediated through ROS-induced oxidative reactions, and PAM treatment exhibited greater cytotoxicity in 2D culture compared to 3D culture. As compared to 2D, the 3D cell culture model provides a viable in vitro cell model for studying the mechanisms of PAM treatment in lung cancer. PAM represents an effective new treatment for NSCLC. Full article

(This article belongs to the Special Issue Challenges and Future Perspectives in Treatment for Lung Cancer)

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Review

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31 pages, 836 KiB

Open AccessReview

Strategies to Overcome Resistance to Osimertinib in EGFR-Mutated Lung Cancer

by Donatella Romaniello, Alessandra Morselli and Ilaria Marrocco

Int. J. Mol. Sci. 2025, 26(7), 2957; https://doi.org/10.3390/ijms26072957 - 25 Mar 2025

Viewed by 879

Abstract

Non-small-cell lung cancer (NSCLC) represents the most common type of lung cancer. The majority of patients with lung cancer characterized by activating mutations in the epidermal growth factor receptor (EGFR), benefit from therapies entailing tyrosine kinase inhibitors (TKIs). In this regard, osimertinib, a third-generation EGFR TKI, has greatly improved the outcome for patients with EGFR-mutated lung cancer. The AURA and FLAURA trials displayed the superiority of the third-generation TKI in both first- and second-line settings, making it the drug of choice for treating patients with EGFR-mutated lung cancer. Unfortunately, the onset of resistance is almost inevitable. On-target mechanisms of resistance include new mutations (e.g., C797S) in the kinase domain of EGFR, while among the off-target mechanisms, amplification of MET or HER2, mutations in downstream signaling molecules, oncogenic fusions, and phenotypic changes (e.g., EMT) have been described. This review focuses on the strategies that are currently being investigated, in preclinical and clinical settings, to overcome resistance to osimertinib, including the use of fourth-generation TKIs, PROTACs, bispecific antibodies, and ADCs, as monotherapy and as part of combination therapies. Full article

(This article belongs to the Special Issue Challenges and Future Perspectives in Treatment for Lung Cancer)

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17 pages, 805 KiB

Open AccessReview

Immunotherapy for Elderly Patients with Advanced Non-Small Cell Lung Cancer: Challenges and Perspectives

by Anass Baladi, Hassan Abdelilah Tafenzi, Othmane Zouiten, Leila Afani, Ismail Essaadi, Mohammed El Fadli and Rhizlane Belbaraka

Int. J. Mol. Sci. 2025, 26(5), 2120; https://doi.org/10.3390/ijms26052120 - 27 Feb 2025

Cited by 1 | Viewed by 866

Abstract

Lung cancer, a leading cause of cancer-related mortality, disproportionately affects the elderly, who face unique challenges due to comorbidities and reduced organ function. Immune checkpoint inhibitors (ICIs) offer a more tolerable alternative to chemotherapy, but their efficacy and safety in elderly non-small cell lung cancer (NSCLC) patients remain underexplored due to limited representation in clinical trials. A narrative literature review was conducted using PubMed, Embase, and the Cochrane Library to evaluate studies on elderly NSCLC patients (≥65 years) treated with ICIs. Key outcomes assessed included overall survival, progression-free survival, response rates, treatment-related adverse events, and the influence of immunosenescence on treatment efficacy. The review highlighted evidence supporting the efficacy and safety of ICIs in elderly NSCLC patients, particularly those with good performance status. Age-related immunosenescence may affect outcomes, emphasizing the need for individualized treatment. Limited data suggest ICIs alone may be preferable to chemo-immunotherapy for patients over 75 years. However, the exclusion of elderly patients from clinical trials and methodological limitations reduces the generalizability of these findings. ICIs hold promise for advanced NSCLC in older adults, but tailored approaches and greater elderly inclusion in trials are needed to optimize outcomes. Full article

(This article belongs to the Special Issue Challenges and Future Perspectives in Treatment for Lung Cancer)

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25 pages, 2416 KiB

Open AccessReview

The Impact of Genetic Mutations on the Efficacy of Immunotherapies in Lung Cancer

by Ki Lui, Kwok-Kuen Cheung, Winnie Wing-Man Ng, Yanping Wang, Doreen W. H. Au and William C. Cho

Int. J. Mol. Sci. 2024, 25(22), 11954; https://doi.org/10.3390/ijms252211954 - 7 Nov 2024

Viewed by 2896

Abstract

Lung cancer is the leading cause of cancer-related mortality worldwide, primarily driven by genetic mutations. The most common genetic alterations implicated in lung cancer include mutations in TP53, KRAS, KEAP1, NF1, EGFR, NRF2, ATM, ALK, Rb1, BRAF, MET, and ERBB2. Targeted therapies have been developed to inhibit cancer growth by focusing on these specific genetic mutations. However, either the mutations are undruggable or the efficacy of these therapies is often compromised over time due to the emergence of drug resistance, which can occur through additional mutations in the targeted protein or alternative growth signaling pathways. In recent years, immunotherapy has emerged as a promising approach to enhance the effectiveness of cancer treatment by leveraging the body’s immune system. Notable advancements include immune checkpoint inhibitors, monoclonal antibodies targeting cell surface receptors, antibody–drug conjugates, and bispecific antibodies. This review provides an overview of the mechanisms of FDA-approved immunotherapeutic drugs, offering an updated perspective on the current state and future developments in lung cancer therapy. More importantly, the factors that positively and negatively impact the immunotherapy’s efficacy will also be discussed. Full article

(This article belongs to the Special Issue Challenges and Future Perspectives in Treatment for Lung Cancer)

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