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Lung Cancer: From Molecular Mechanisms to Novel Therapeutics

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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 March 2025 | Viewed by 19867

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Special Issue Editors

Dr. Mariacarmela Santarpia

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Guest Editor

1. Medical Oncology Unit, AOU Policlinico "G.Martino", 98125 Messina, Italy
2. Department of Human Pathology “G. Barresi”, University of Messina, 98122 Messina, Italy
Interests: lung cancer; targeted therapy; immunotherapy; personalized medicine; biomarkers
Special Issues, Collections and Topics in MDPI journals

Dr. Giulia Pasello

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Guest Editor

1. Medical Oncology 2, Istituto Oncologico Veneto IRCCS, 35128 Padova, Italy
2. Department of Surgery, Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy
Interests: lung cancer; mesothelioma; targeted therapy; immunotherapy; biomarkers

Special Issue Information

Dear Colleagues,

Lung cancer remains the most significant cause of cancer-related deaths worldwide. Both molecular-targeted therapy and immunotherapy have revolutionized the diagnostic and therapeutic management of this heterogenous disease, which includes different histologic and molecular subtypes. The number of actionable oncogenic drivers continues to expand, in parallel with the development of novel targeted agents. On the other hand, several immune checkpoint inhibitors, as single agents or in combinatorial regimens, have been approved in metastatic non-small-cell lung cancer without targetable molecular alterations because of the demonstration of significant clinical efficacy and manageable toxicity profiles. Their development has been shifted in the early stages, with promising results. However, despite significant therapeutic advances, several challenges still remain, including the need for additional reliable biomarkers to select patients for immunotherapy, and a better understanding of the complex biologic mechanisms leading to therapeutic resistance. This Special Issue will focus on: a) identification of new druggable driver gene alterations in lung cancer; b) development of new drugs and combination therapies targeting specific molecular pathways; c) current knowledge on primary and secondary mechanisms of resistance to targeted therapies or immunotherapy; d) current and emerging techniques to identify predictive biomarkers in tissue and liquid biopsy.

Dr. Mariacarmela Santarpia
Dr. Giulia Pasello
Guest Editors

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Keywords

lung cancer
oncogene
targeted therapy
immunotherapy
predictive biomarkers
liquid biopsy

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Published Papers (8 papers)

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Research

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20 pages, 3739 KiB

Open AccessArticle

Hsp70 Negatively Regulates Autophagy via Governing AMPK Activation, and Dual Hsp70-Autophagy Inhibition Induces Synergetic Cell Death in NSCLC Cells

by Bashar Alhasan, Yana A. Gladova, Dmitry V. Sverchinsky, Nikolai D. Aksenov, Boris A. Margulis and Irina V. Guzhova

Int. J. Mol. Sci. 2024, 25(16), 9090; https://doi.org/10.3390/ijms25169090 - 22 Aug 2024

Viewed by 1156

Abstract

Proteostasis mechanisms, such as proteotoxic-stress response and autophagy, are increasingly recognized for their roles in influencing various cancer hallmarks such as tumorigenesis, drug resistance, and recurrence. However, the precise mechanisms underlying their coordination remain not fully elucidated. The aim of this study is to investigate the molecular interplay between Hsp70 and autophagy in lung adenocarcinoma cells and elucidate its impact on the outcomes of anticancer therapies in vitro. For this purpose, we utilized the human lung adenocarcinoma A549 cell line and genetically modified it by knockdown of Hsp70 or HSF1, and the H1299 cell line with knockdown or overexpression of Hsp70. In addition, several treatments were employed, including treatment with Hsp70 inhibitors (VER-155008 and JG-98), HSF1 activator ML-346, or autophagy modulators (SAR405 and Rapamycin). Using immunoblotting, we found that Hsp70 negatively regulates autophagy by directly influencing AMPK activation, uncovering a novel regulatory mechanism of autophagy by Hsp70. Genetic or chemical Hsp70 overexpression was associated with the suppression of AMPK and autophagy. Conversely, the inhibition of Hsp70, genetically or chemically, resulted in the upregulation of AMPK-mediated autophagy. We further investigated whether Hsp70 suppression-mediated autophagy exhibits pro-survival- or pro-death-inducing effects via MTT test, colony formation, CellTiter-Glo 3D-Spheroid viability assay, and Annexin/PI apoptosis assay. Our results show that combined inhibition of Hsp70 and autophagy, along with cisplatin treatment, synergistically reduces tumor cell metabolic activity, growth, and viability in 2D and 3D tumor cell models. These cytotoxic effects were exerted by substantially potentiating apoptosis, while activating autophagy via rapamycin slightly rescued tumor cells from apoptosis. Therefore, our findings demonstrate that the combined inhibition of Hsp70 and autophagy represents a novel and promising therapeutic approach that may disrupt the capacity of refractory tumor cells to withstand conventional therapies in NSCLC. Full article

(This article belongs to the Special Issue Lung Cancer: From Molecular Mechanisms to Novel Therapeutics)

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18 pages, 9873 KiB

Open AccessArticle

The Roles and Regulatory Mechanisms of Tight Junction Protein Cingulin and Transcription Factor Forkhead Box Protein O1 in Human Lung Adenocarcinoma A549 Cells and Normal Lung Epithelial Cells

by Daichi Ishii, Yuma Shindo, Wataru Arai, Takumi Konno, Takayuki Kohno, Kazuya Honda, Masahiro Miyajima, Atsushi Watanabe and Takashi Kojima

Int. J. Mol. Sci. 2024, 25(3), 1411; https://doi.org/10.3390/ijms25031411 - 24 Jan 2024

Cited by 2 | Viewed by 1631

Abstract

Tight junction (TJ) protein cingulin (CGN) and transcription factor forkhead box protein O1 (FOXO1) contribute to the development of various cancers. Histone deacetylase (HDAC) inhibitors have a potential therapeutic role for some cancers. HDAC inhibitors affect the expression of both CGN and FOXO1. However, the roles and regulatory mechanisms of CGN and FOXO1 are unknown in non-small cell lung cancer (NSCLC) and normal human lung epithelial (HLE) cells. In the present study, to investigate the effects of CGN and FOXO1 on the malignancy of NSCLC, we used A549 cells as human lung adenocarcinoma and primary human lung epithelial (HLE) cells as normal lung tissues and performed the knockdown of CGN and FOXO1 by siRNAs. Furthermore, to investigate the detailed mechanisms in the antitumor effects of HDAC inhibitors for NSCLC via CGN and FOXO1, A549 cells and HLE cells were treated with the HDAC inhibitors trichostatin A (TSA) and Quisinostat (JNJ-2648158). In A549 cells, the knockdown of CGN increased bicellular TJ protein claudin-2 (CLDN-2) via mitogen-activated protein kinase/adenosine monophosphate-activated protein kinase (MAPK/AMPK) pathways and induced cell migration, while the knockdown of FOXO1 increased claudin-4 (CLDN-4), decreased CGN, and induced cell proliferation. The knockdown of CGN and FOXO1 induced cell metabolism in A549 cells. TSA and Quisinostat increased CGN and tricellular TJ protein angulin-1/lipolysis-stimulated lipoprotein receptor (LSR) in A549. In normal HLE cells, the knockdown of CGN and FOXO1 increased CLDN-4, while HDAC inhibitors increased CGN and CLDN-4. In conclusion, the knockdown of CGN via FOXO1 contributes to the malignancy of NSCLC. Both HDAC inhibitors, TSA and Quisinostat, may have potential for use in therapy for lung adenocarcinoma via changes in the expression of CGN and FOXO1. Full article

(This article belongs to the Special Issue Lung Cancer: From Molecular Mechanisms to Novel Therapeutics)

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25 pages, 5296 KiB

Open AccessArticle

Real-World Data on Combined EGFR-TKI and Crizotinib Treatment for Acquired and De Novo MET Amplification in Patients with Metastatic EGFR-Mutated NSCLC

by Edyta M. Urbanska, Morten Grauslund, Peter R. Koffeldt, Sarah L. B. Truelsen, Johan O. Löfgren, Junia C. Costa, Linea C. Melchior, Jens B. Sørensen and Eric Santoni-Rugiu

Int. J. Mol. Sci. 2023, 24(17), 13077; https://doi.org/10.3390/ijms241713077 - 23 Aug 2023

Cited by 3 | Viewed by 2193

Abstract

Amplification of the mesenchymal epithelial transition (MET) gene is a mechanism of acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine-kinase-inhibitors (TKIs) in over 20% of patients with advanced EGFR-mutated (EGFRm+) non-small lung cancer (NSCLC). However, it may also occur de novo in 2–8% of EGFRm+ NSCLC cases as a potential mechanism of intrinsic resistance. These patients represent a group with unmet needs, since there is no standard therapy currently approved. Several new MET inhibitors are being investigated in clinical trials, but the results are awaited. Meanwhile, as an alternative strategy, combinations of EGFR-TKIs with the MET/ALK/ROS1-TKI Crizotinib may be used in this setting, despite this use is principally off-label. Thus, we studied five of these MET amplified cases receiving EGFR-TKI and Crizotinib doublet after progression on EGFR-TKI treatment to assess the benefits and challenges related to this combination and the possible occurrence of genomic and phenotypic co-alterations. Furthermore, we compared our cases with other real-world reports on Crizotinib/EGFR-TKI combinations, which appeared effective, especially in patients with high-level MET amplification. Yet, we observed that the co-occurrence of other genomic and phenotypical alterations may affect the response to combined EGFR-TKI and Crizotinib. Finally, given the heterogeneity of MET amplification, the diagnostic methods for assessing it may be discrepant. In this respect, we observed that for optimal detection, immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing should be used together, as these methods possess different sensitivities and complement each other in characterizing MET amplification. Additionally, we addressed the issue of managing EGFR-mutated NSCLC patients with de novo MET amplification causing primary EGFR-TKI resistance. We conclude that, while data from clinical trials with new MET inhibitors are still pending, adding Crizotinib to EGFR-TKI in NSCLC patients acquiring MET amplification at progression on EGFR-TKI monotherapy is a reasonable approach, with a progression-free survival of 3–19 months. Full article

(This article belongs to the Special Issue Lung Cancer: From Molecular Mechanisms to Novel Therapeutics)

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Review

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15 pages, 618 KiB

Open AccessReview

Treatment of Thoracic SMARCA4-Deficient Undifferentiated Tumors: Where We Are and Where We Will Go

by Vito Longo, Annamaria Catino, Michele Montrone, Elisabetta Sara Montagna, Francesco Pesola, Ilaria Marech, Pamela Pizzutilo, Annalisa Nardone, Antonella Perrone, Monica Gesualdo and Domenico Galetta

Int. J. Mol. Sci. 2024, 25(6), 3237; https://doi.org/10.3390/ijms25063237 - 13 Mar 2024

Cited by 4 | Viewed by 3245

Abstract

Recently, the fifth edition of the WHO classification recognized the thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) as a separate entity from conventional non-small cell lung cancer with SMARCA4 deficiency because of the different clinicopathological characteristics of these two diseases. SMARCA4-UT mainly occurs in young to middle-aged adults and involves a large mass compressing the tissues surrounding the mediastinum and lung parenchyma. Unfortunately, SMARCA4-UT shows a high probability of recurrence after upfront surgery as well as radiotherapy resistance; moreover, chemotherapy has low efficacy. Moreover, given the recent classification of SMARCA4-UT, no data concerning specific clinical trials are currently available. However, several case reports show immunotherapy efficacy in patients with this disease not only in a metastatic setting but also in a neoadjuvant manner, supporting the development of clinical trials. In addition, preclinical data and initial clinical experiences suggest that inhibiting pathways such as CDK4/6, AURKA, ATR, and EZH2 may be a promising therapeutic approach to SMARCA4-UT. Full article

(This article belongs to the Special Issue Lung Cancer: From Molecular Mechanisms to Novel Therapeutics)

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26 pages, 1031 KiB

Open AccessReview

Targeting MET in Non-Small Cell Lung Cancer (NSCLC): A New Old Story?

by Calogera Claudia Spagnolo, Giuliana Ciappina, Elisa Giovannetti, Andrea Squeri, Barbara Granata, Chiara Lazzari, Giulia Pretelli, Giulia Pasello and Mariacarmela Santarpia

Int. J. Mol. Sci. 2023, 24(12), 10119; https://doi.org/10.3390/ijms241210119 - 14 Jun 2023

Cited by 6 | Viewed by 3745

Abstract

In recent years, we have seen the development and approval for clinical use of an increasing number of therapeutic agents against actionable oncogenic drivers in metastatic non-small cell lung cancer (NSCLC). Among them, selective inhibitors, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies targeting the mesenchymal–epithelial transition (MET) receptor, have been studied in patients with advanced NSCLC with MET deregulation, primarily due to exon 14 skipping mutations or MET amplification. Some MET TKIs, including capmatinib and tepotinib, have proven to be highly effective in this molecularly defined subgroup of patients and are already approved for clinical use. Other similar agents are being tested in early-stage clinical trials with promising antitumor activity. The purpose of this review is to provide an overview of MET signaling pathways, MET oncogenic alterations primarily focusing on exon 14 skipping mutations, and the laboratory techniques used to detect MET alterations. Furthermore, we will summarize the currently available clinical data and ongoing studies on MET inhibitors, as well as the mechanisms of resistance to MET TKIs and new potential strategies, including combinatorial approaches, to improve the clinical outcomes of MET exon 14-altered NSCLC patients. Full article

(This article belongs to the Special Issue Lung Cancer: From Molecular Mechanisms to Novel Therapeutics)

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19 pages, 303 KiB

Open AccessReview

Targeted Toxicities: Protocols for Monitoring the Adverse Events of Targeted Therapies Used in the Treatment of Non-Small Cell Lung Cancer

by Jacobi B. Hines, Benjamin Bowar, Emma Levine, Alessandra Esposito, Marina C. Garassino and Christine M. Bestvina

Int. J. Mol. Sci. 2023, 24(11), 9429; https://doi.org/10.3390/ijms24119429 - 29 May 2023

Cited by 4 | Viewed by 2171

Abstract

Targeted therapies have revolutionized the treatment for many patients with non-small cell lung cancer (NSCLC). Multiple new oral targeted therapies have been approved in the last decade; however, their overall efficacy may be reduced by poor adherence, treatment interruptions, or dose reductions due to adverse events. Most institutions lack standard monitoring protocols for toxicities from these targeted agents. This review describes important adverse events observed in clinical trials and reported by the U.S. Food and Drug Administration for both currently approved and upcoming promising therapies in the treatment of NSCLC. These agents cause a range of toxicities, including dermatologic, gastroenteric, pulmonary, and cardiac toxicities. This review proposes protocols for routine monitoring of these adverse events, both prior to initiation of therapy and while on treatment. Full article

(This article belongs to the Special Issue Lung Cancer: From Molecular Mechanisms to Novel Therapeutics)

21 pages, 2199 KiB

Open AccessReview

Overview on Therapeutic Options in Uncommon EGFR Mutant Non-Small Cell Lung Cancer (NSCLC): New Lights for an Unmet Medical Need

by Giulia Pretelli, Calogera Claudia Spagnolo, Giuliana Ciappina, Mariacarmela Santarpia and Giulia Pasello

Int. J. Mol. Sci. 2023, 24(10), 8878; https://doi.org/10.3390/ijms24108878 - 17 May 2023

Cited by 11 | Viewed by 3132

Abstract

The majority of epidermal growth factor receptor (EGFR) mutations (85–90%) are exon 19 deletions and L858R point mutations of exon 21, characterized by high sensitivity to EGFR-tyrosine kinase inhibitors (TKIs). Less is known about uncommon mutations (10–15% of EGFR mutations). The predominant mutation types in this category include exon 18 point mutations, exon 21 L861X, exon 20 insertions, and exon 20 S768I. This group shows a heterogeneous prevalence, partly due to different testing methods and to the presence of compound mutations, which in some cases can lead to shorter overall survival and different sensitivity to different TKIs compared to simple mutations. Additionally, EGFR-TKI sensitivity may also vary depending on the specific mutation and the tertiary structure of the protein. The best strategy remains uncertain, and the data of EGFR-TKIs efficacy are based on few prospective and some retrospective series. Newer investigational agents are still under study, and there are no other approved specific treatments targeting uncommon EGFR mutations. Defining the best treatment option for this patient population remains an unmet medical need. The objective of this review is to evaluate existing data on the outcomes, epidemiology, and clinical characteristics of lung cancer patients with rare EGFR mutations, with a focus on intracranial activity and response to immunotherapy. Full article

(This article belongs to the Special Issue Lung Cancer: From Molecular Mechanisms to Novel Therapeutics)

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14 pages, 1723 KiB

Open AccessBrief Report

Membrane Localization and Phosphorylation of Indoleamine 2,3-Dioxygenase 2 (IDO2) in A549 Human Lung Adenocarcinoma Cells: First Steps in Exploring Its Signaling Function

by Chiara Suvieri, Francesca De Marchis, Martina Mandarano, Sara Ambrosino, Sofia Rossini, Giada Mondanelli, Marco Gargaro, Eleonora Panfili, Ciriana Orabona, Maria Teresa Pallotta, Maria Laura Belladonna and Claudia Volpi

Int. J. Mol. Sci. 2023, 24(22), 16236; https://doi.org/10.3390/ijms242216236 - 12 Nov 2023

Cited by 1 | Viewed by 1679

Abstract

Indoleamine 2,3-dioxygenase 2 (IDO2) is a paralog of Indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan-degrading enzyme producing immunomodulatory molecules. However, the two proteins are unlikely to carry out the same functions. IDO2 shows little or no tryptophan catabolic activity and exerts contrasting immunomodulatory roles in a context-dependent manner in cancer and autoimmune diseases. The recently described potential non-enzymatic activity of IDO2 has suggested its possible involvement in alternative pathways, resulting in either pro- or anti-inflammatory effects in different models. In a previous study on non-small cell lung cancer (NSCLC) tissues, we found that IDO2 expression revealed at the plasma membrane level of tumor cells was significantly associated with poor prognosis. In this study, the A549 human cell line, basally expressing IDO2, was used as an in vitro model of human lung adenocarcinoma to gain more insights into a possible alternative function of IDO2 different from the catalytic one. In these cells, immunocytochemistry and isopycnic sucrose gradient analyses confirmed the IDO2 protein localization in the cell membrane compartment, and the immunoprecipitation of tyrosine-phosphorylated proteins revealed that kinase activities can target IDO2. The different localization from the cytosolic one and the phosphorylation state are the first indications for the signaling function of IDO2, suggesting that the IDO2 non-enzymatic role in cancer cells is worthy of deeper understanding. Full article

(This article belongs to the Special Issue Lung Cancer: From Molecular Mechanisms to Novel Therapeutics)

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