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Cancers
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Lung Cancer: Targeted Therapy and Immunotherapy
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Lung Cancer: Targeted Therapy and Immunotherapy

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

Deadline for manuscript submissions: closed (15 October 2021) | Viewed by 43390

Special Issue Editor

Dr. Noriaki Sunaga

E-Mail Website
Guest Editor
Department of Respiratory Medicine, Gunma University Graduate School of Medicine, 3-39-15, Showa-machi, Maebashi 371-8511, Japan
Interests: lung cancer; molecular biology; molecular targeted therapy; immunotherapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Lung cancer is the leading cause of cancer-related death in the world. Lung cancer is divided into two main subtypes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Recent advances in molecular biology have uncovered several druggable oncogenes driving NSCLC, and molecularly targeted drugs, such as EGFR–tyrosine kinase inhibitors, have prolonged survival in patients with NSCLC. However, most patients ultimately develop recurrence due to the acquisition of resistance to molecularly targeted drugs, making such patients difficult to cure.

The development of immune checkpoint inhibitors (ICIs), including anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibodies, represents a milestone in the oncology field. Therapeutic approaches with ICIs have been introduced to treat patients with both SCLC and NSCLC; however, in order to achieve durable responses to ICIs, there remains an urgent need to identify biomarkers and resistance mechanisms.

This Special Issue will highlight current advances in and future research directions of molecularly targeted therapy and immunotherapy in lung cancer. We welcome both preclinical and clinical studies whose findings lead to a better understanding of this rapidly evolving field.

Dr. Noriaki Sunaga
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

  • small cell lung cancer
  • non-small cell lung cancer
  • driver oncogenes
  • molecularly targeted drugs
  • immune checkpoint inhibitors
  • resistance mechanisms

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Published Papers (8 papers)

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Research

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16 pages, 9513 KiB  
Article
Molecular Signature of Small Cell Lung Cancer after Treatment Failure: The MCM Complex as Therapeutic Target
by Shunsuke Misono, Keiko Mizuno, Takayuki Suetsugu, Kengo Tanigawa, Nijiro Nohata, Akifumi Uchida, Hiroki Sanada, Reona Okada, Shogo Moriya, Hiromasa Inoue and Naohiko Seki
Cancers 2021, 13(6), 1187; https://doi.org/10.3390/cancers13061187 - 10 Mar 2021
Cited by 12 | Viewed by 3450
Abstract
Small cell lung cancer (SCLC) is a highly aggressive cancer, and patients who become refractory to first-line treatment have a poor prognosis. The development of effective treatment regimens is urgently needed. In this study, we identified a gene expression signature of SCLC after [...] Read more.
Small cell lung cancer (SCLC) is a highly aggressive cancer, and patients who become refractory to first-line treatment have a poor prognosis. The development of effective treatment regimens is urgently needed. In this study, we identified a gene expression signature of SCLC after treatment failure using SCLC clinical specimens (GEO accession number: GSE162102). A total of 1,136 genes were significantly upregulated in SCLC tissues. These upregulated genes were subjected to KEGG pathway analysis, and “cell cycle”, “Fanconi anemia”, “alcoholism”, “systemic lupus erythematosus”, “oocyte meiosis”, “homologous recombination”, “DNA replication”, and “p53 signaling” were identified as the enriched pathways among the genes. We focused on the cell cycle pathway and investigated the clinical significance of four genes associated with this pathway: minichromosome maintenance (MCM) 2, MCM4, MCM6, and MCM7. The overexpression of these MCM genes was confirmed in SCLC clinical specimens. Knockdown assays using siRNAs targeting each of these four MCM genes showed significant attenuation of cancer cell proliferation. Moreover, siRNA-mediated knockdown of each MCM gene enhanced the cisplatin sensitivity of SCLC cells. Our SCLC molecular signature based on SCLC clinical specimens after treatment failure will provide useful information to identify novel molecular targets for this disease. Full article
(This article belongs to the Special Issue Lung Cancer: Targeted Therapy and Immunotherapy)
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Review

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18 pages, 665 KiB  
Review
Treatment Strategies for Non-Small Cell Lung Cancer Harboring Common and Uncommon EGFR Mutations: Drug Sensitivity Based on Exon Classification, and Structure-Function Analysis
by Rui Kitadai and Yusuke Okuma
Cancers 2022, 14(10), 2519; https://doi.org/10.3390/cancers14102519 - 20 May 2022
Cited by 13 | Viewed by 6415
Abstract
The identification of epidermal growth factor receptor (EGFR) mutations and development of EGFR tyrosine kinase inhibitors (EGFR-TKIs) have dramatically improved the prognosis of advanced EGFR-mutated non-small cell lung cancer (NSCLC), setting a landmark in precision oncology. Exon 19 deletions and exon [...] Read more.
The identification of epidermal growth factor receptor (EGFR) mutations and development of EGFR tyrosine kinase inhibitors (EGFR-TKIs) have dramatically improved the prognosis of advanced EGFR-mutated non-small cell lung cancer (NSCLC), setting a landmark in precision oncology. Exon 19 deletions and exon 21 L858R substitutions, which comprise the majority of common EGFR mutations, are predictors of good sensitivity to EGFR-TKIs. However, not all cancers harboring EGFR mutations are sensitive to EGFR-TKIs. Most patients harboring uncommon EGFR mutations demonstrate a poorer clinical response than those harboring common EGFR mutations. For example, cancers harboring exon 20 insertions, which represent approximately 4–12% of EGFR mutations, are generally insensitive to first- and second-generation EGFR-TKIs. Although understanding the biology of uncommon EGFR mutations is essential for developing treatment strategies, there is little clinical data because of their rarity. Moreover, clarifying the acquired resistance of EGFR-mutated NSCLC may lead to more precise treatments. Sequencing and structure-based analyses of EGFRmutated NSCLC have revealed resistance mechanisms and drug sensitivity. In this review, we discuss the strategies in development for treating NSCLC harboring common and uncommon EGFR mutations. We will also focus on EGFR-TKI sensitivity in patients harboring EGFR mutations based on the structural features. Full article
(This article belongs to the Special Issue Lung Cancer: Targeted Therapy and Immunotherapy)
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15 pages, 716 KiB  
Review
A Promising Treatment Strategy for Lung Cancer: A Combination of Radiotherapy and Immunotherapy
by Yuhei Miyasaka, Hiro Sato, Naoko Okano, Nobuteru Kubo, Hidemasa Kawamura and Tatsuya Ohno
Cancers 2022, 14(1), 203; https://doi.org/10.3390/cancers14010203 - 31 Dec 2021
Cited by 9 | Viewed by 3004
Abstract
Lung cancer is a leading cause of cancer-related deaths worldwide despite advances in treatment. In the past few decades, radiotherapy has achieved outstanding technical advances and is being widely used as a definitive, prophylactic, or palliative treatment of patients with lung cancer. The [...] Read more.
Lung cancer is a leading cause of cancer-related deaths worldwide despite advances in treatment. In the past few decades, radiotherapy has achieved outstanding technical advances and is being widely used as a definitive, prophylactic, or palliative treatment of patients with lung cancer. The anti-tumor effects of radiotherapy are considered to result in DNA damage in cancer cells. Moreover, recent evidence has demonstrated another advantage of radiotherapy: the induction of anti-tumor immune responses, which play an essential role in cancer control. In contrast, radiotherapy induces an immunosuppressive response. These conflicting reactions after radiotherapy suggest that maximizing immune response to radiotherapy by combining immunotherapy has potential to achieve more effective anti-tumor response than using each alone. Immune checkpoint molecules, such as cytotoxic T-lymphocyte-associated protein 4, programmed cell death-1/programmed death-ligand 1, and their inhibitors, have attracted significant attention for overcoming the immunosuppressive conditions in patients with cancer. Therefore, the combination of immune checkpoint inhibitors and radiotherapy is promising. Emerging preclinical and clinical studies have demonstrated the rationale for these combination strategies. In this review, we outlined evidence suggesting that combination of radiotherapy, including particle therapy using protons and carbon ions, with immunotherapy in lung cancer treatment could be a promising treatment strategy. Full article
(This article belongs to the Special Issue Lung Cancer: Targeted Therapy and Immunotherapy)
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13 pages, 962 KiB  
Review
Targeting Oncogenic KRAS in Non-Small-Cell Lung Cancer
by Noriaki Sunaga, Yosuke Miura, Norimitsu Kasahara and Reiko Sakurai
Cancers 2021, 13(23), 5956; https://doi.org/10.3390/cancers13235956 - 26 Nov 2021
Cited by 15 | Viewed by 7049
Abstract
Recent advances in molecular biology and the resultant identification of driver oncogenes have achieved major progress in precision medicine for non-small-cell lung cancer (NSCLC). v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) is the most common driver in NSCLC, and targeting KRAS [...] Read more.
Recent advances in molecular biology and the resultant identification of driver oncogenes have achieved major progress in precision medicine for non-small-cell lung cancer (NSCLC). v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) is the most common driver in NSCLC, and targeting KRAS is considerably important. The recent discovery of covalent KRAS G12C inhibitors offers hope for improving the prognosis of NSCLC patients, but the development of combination therapies corresponding to tumor characteristics is still required given the vast heterogeneity of KRAS-mutated NSCLC. In this review, we summarize the current understanding of KRAS mutations regarding the involvement of malignant transformation and describe the preclinical and clinical evidence for targeting KRAS-mutated NSCLC. We also discuss the mechanisms of resistance to KRAS G12C inhibitors and possible combination treatment strategies to overcome this drug resistance. Full article
(This article belongs to the Special Issue Lung Cancer: Targeted Therapy and Immunotherapy)
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26 pages, 1819 KiB  
Review
Targeting MERTK and AXL in EGFR Mutant Non-Small Cell Lung Cancer
by Dan Yan, H. Shelton Earp, Deborah DeRyckere and Douglas K. Graham
Cancers 2021, 13(22), 5639; https://doi.org/10.3390/cancers13225639 - 11 Nov 2021
Cited by 19 | Viewed by 5432
Abstract
MERTK and AXL are members of the TAM family of receptor tyrosine kinases and are abnormally expressed in 69% and 93% of non-small cell lung cancers (NSCLCs), respectively. Expression of MERTK and/or AXL provides a survival advantage for NSCLC cells and correlates with [...] Read more.
MERTK and AXL are members of the TAM family of receptor tyrosine kinases and are abnormally expressed in 69% and 93% of non-small cell lung cancers (NSCLCs), respectively. Expression of MERTK and/or AXL provides a survival advantage for NSCLC cells and correlates with lymph node metastasis, drug resistance, and disease progression in patients with NSCLC. The TAM receptors on host tumor infiltrating cells also play important roles in the immunosuppressive tumor microenvironment. Thus, MERTK and AXL are attractive biologic targets for NSCLC treatment. Here, we will review physiologic and oncologic roles for MERTK and AXL with an emphasis on the potential to target these kinases in NSCLCs with activating EGFR mutations. Full article
(This article belongs to the Special Issue Lung Cancer: Targeted Therapy and Immunotherapy)
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16 pages, 549 KiB  
Review
Surgery after Induction Targeted Therapy and Immunotherapy for Lung Cancer
by Toon Allaeys, Lawek Berzenji and Paul E. Van Schil
Cancers 2021, 13(11), 2603; https://doi.org/10.3390/cancers13112603 - 26 May 2021
Cited by 13 | Viewed by 2890
Abstract
Multimodality therapy for locally advanced non-small cell lung cancer (NSCLC) is a complex and controversial issue, especially regarding optimal treatment regimens for patients with ipsilateral positive mediastinal nodes (N2 disease). Many trials investigating neoadjuvant immunotherapy and targeted therapy in this subpopulation have shown [...] Read more.
Multimodality therapy for locally advanced non-small cell lung cancer (NSCLC) is a complex and controversial issue, especially regarding optimal treatment regimens for patients with ipsilateral positive mediastinal nodes (N2 disease). Many trials investigating neoadjuvant immunotherapy and targeted therapy in this subpopulation have shown promising results, although concerns have risen regarding surgical feasibility. A thorough literature review was performed, analyzing all recent studies regarding surgical morbidity and mortality. Despite the fact that two major trials investigating this subject were terminated early, the overall consensus is that surgical management seems feasible. However, dissection of hilar vessels may be challenging due to hilar fibrosis. Further research is necessary to identify the role of surgery in these multimodality treatment regimens, and to define matters such as the optimal treatment regimen, the dosage of the different agents used, the interval between induction therapy and surgery, and the role of adjuvant therapy. Full article
(This article belongs to the Special Issue Lung Cancer: Targeted Therapy and Immunotherapy)
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23 pages, 1530 KiB  
Review
Chasing the Target: New Phenomena of Resistance to Novel Selective RET Inhibitors in Lung Cancer. Updated Evidence and Future Perspectives
by Sara Fancelli, Enrico Caliman, Francesca Mazzoni, Marco Brugia, Francesca Castiglione, Luca Voltolini, Serena Pillozzi and Lorenzo Antonuzzo
Cancers 2021, 13(5), 1091; https://doi.org/10.3390/cancers13051091 - 4 Mar 2021
Cited by 26 | Viewed by 4698
Abstract
The potent, RET-selective tyrosine kinase inhibitors (TKIs) pralsetinib and selpercatinib, are effective against the RET V804L/M gatekeeper mutants, however, adaptive mutations that cause resistance at the solvent front RET G810 residue have been found, pointing to the need for the development of the [...] Read more.
The potent, RET-selective tyrosine kinase inhibitors (TKIs) pralsetinib and selpercatinib, are effective against the RET V804L/M gatekeeper mutants, however, adaptive mutations that cause resistance at the solvent front RET G810 residue have been found, pointing to the need for the development of the next-generation of RET-specific TKIs. Also, as seen in EGFR- and ALK-driven NSCLC, the rising of the co-occurring amplifications of KRAS and MET could represent other escaping mechanisms from direct inhibition. In this review, we summarize actual knowledge on RET fusions, focusing on those involved in NSCLC, the results of main clinical trials of approved RET-inhibition drugs, with particular attention on recent published results of selective TKIs, and finally, pre-clinical evidence regarding resistance mechanisms and suggestion on hypothetical and feasible drugs combinations and strategies viable in the near future. Full article
(This article belongs to the Special Issue Lung Cancer: Targeted Therapy and Immunotherapy)
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13 pages, 814 KiB  
Review
HER2-/HER3-Targeting Antibody—Drug Conjugates for Treating Lung and Colorectal Cancers Resistant to EGFR Inhibitors
by Kimio Yonesaka
Cancers 2021, 13(5), 1047; https://doi.org/10.3390/cancers13051047 - 2 Mar 2021
Cited by 33 | Viewed by 9034
Abstract
Epidermal growth factor receptor (EGFR) is one of the anticancer drug targets for certain malignancies, including nonsmall cell lung cancer (NSCLC), colorectal cancer (CRC), and head and neck squamous cell carcinoma. However, the grave issue of drug resistance through diverse mechanisms persists, including [...] Read more.
Epidermal growth factor receptor (EGFR) is one of the anticancer drug targets for certain malignancies, including nonsmall cell lung cancer (NSCLC), colorectal cancer (CRC), and head and neck squamous cell carcinoma. However, the grave issue of drug resistance through diverse mechanisms persists, including secondary EGFR-mutation and its downstream RAS/RAF mutation. Since the discovery of the role of human epidermal growth factor receptor 2 (HER2) and HER3 in drug resistance, HER2- or HER3-targeting treatment strategies using monoclonal antibodies have been intensively examined and have demonstrated impressive responsiveness and limitations. Finally, an innovative targeted therapy called antibody drug conjugates (ADC) has provided a solution to overcome this resistance. Specifically, a new cleavable linker-payload system enables stable drug delivery to cancer cells, causing selective destruction. HER2-targeting ADC trastuzumab deruxtecan demonstrated promising responsiveness in patients with HER2-positive CRC, in a phase 2 clinical trial (objective response rate = 45.3%). Furthermore, HER3-targeting patritumab deruxtecan, another ADC, exhibited impressive tumor shrinkage in pretreated patients with EGFR-mutated NSCLC, in a phase 1 clinical trial. This manuscript presents an overview of the accumulated evidence on HER2- and HER3-targeting therapy, especially ADCs, and discussion of remaining issues for further improving these treatments in cancers resistant to EGFR inhibitors. Full article
(This article belongs to the Special Issue Lung Cancer: Targeted Therapy and Immunotherapy)
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