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Cancers
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New and Emerging Strategies for Targeting Genomic Instability and Overcoming...
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New and Emerging Strategies for Targeting Genomic Instability and Overcoming Drug Resistance in Lung Cancer

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

Deadline for manuscript submissions: closed (30 April 2025) | Viewed by 7590

Special Issue Editor

Dr. Kelsie L. Thu

E-Mail Website
Guest Editor
1. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
2. Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada
Interests: lung cancer; genomic

Special Issue Information

Dear Colleagues,

Advances in targeted therapies and immunotherapies have greatly expanded the treatment landscape for lung cancer, defining opportunities for precision medicine and improving the quality of life and survival rates for patients. Although significant progress has been made, lung cancer recurrence driven by drug resistance to all treatment modalities remains a major clinical barrier to further improving patient outcomes. Genomic instability is a well-established hallmark of lung and other cancers that promotes tumor evolution and the development of drug resistance. However, too much instability can be lethal to cancer cells due to excessive aneuploidy and cellular stress. Thus, genomic instability in cancer is a fine balance between its tumor-promoting advantages and potentially lethal consequences. Given its specificity to malignant cells, potentiating genomic instability to lethal levels could be an effective treatment strategy for combating tumor progression and drug resistance in lung cancer patients. This Special Issue focuses on new developments in targeting genomic instability and therapeutic approaches for overcoming drug resistance in lung cancer.

Dr. Kelsie L. Thu
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
  • genomic instability
  • drug resistance
  • treatment strategy
  • targeted therapy

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Published Papers (5 papers)

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Research

Jump to: Review

34 pages, 5820 KiB  
Article
Identification of Genomic Instability-Associated LncRNAs as Potential Therapeutic Targets in Lung Adenocarcinoma
by Vanessa G. P. Souza, Katya H. Benard, Greg L. Stewart, Katey S. S. Enfield and Wan L. Lam
Cancers 2025, 17(6), 996; https://doi.org/10.3390/cancers17060996 - 15 Mar 2025
Viewed by 785
Abstract
Background/Objectives: Non-small cell lung cancer (NSCLC) is the most common type of cancer, with lung adenocarcinoma (LUAD) as the predominant subtype. Despite advancements in targeted therapies, many NSCLC patients still experience poor outcomes due to treatment resistance and disease progression. Genomic instability (GI), [...] Read more.
Background/Objectives: Non-small cell lung cancer (NSCLC) is the most common type of cancer, with lung adenocarcinoma (LUAD) as the predominant subtype. Despite advancements in targeted therapies, many NSCLC patients still experience poor outcomes due to treatment resistance and disease progression. Genomic instability (GI), a hallmark of cancer, defined as the increased tendency of DNA mutations and alterations, is closely linked to cancer initiation, progression, and resistance to therapy. Emerging evidence suggests that long non-coding RNAs (lncRNAs)—molecules longer than 200 nucleotides that do not encode proteins but regulate gene expression—play critical roles in cancer biology and are associated with GI. However, the relationship between GI and lncRNA expression in LUAD remains poorly understood. Methods: In this study, we analyzed the transcript profiles of lncRNAs and mRNAs from LUAD samples in The Cancer Genome Atlas (TCGA) database and classified them based on their Homologous Recombination Deficiency (HRD) score. The HRD score is an unweighted sum of three independent DNA-based measures of genomic instability: loss of heterozygosity, telomeric allelic imbalance, and large-scale transitions. We then performed a differential gene expression analysis to identify lncRNAs and mRNAs that were either upregulated or downregulated in samples with high HRD scores compared to those with low HRD scores. Following this, we conducted a correlation analysis to assess the significance of the association between HRD scores and the expression of both lncRNAs and mRNAs. Results: We identified 30 differentially expressed lncRNAs and 200 mRNAs associated with genomic instability. Using an RNA interactome database from sequencing experiments, we found evidence of interactions between GI-associated lncRNAs (GI-lncRNAs) and GI-associated mRNAs (GI-mRNAs). Further investigation showed that some GI-lncRNAs play regulatory and functional roles in LUAD and other diseases. We also found that GI-lncRNAs have potential as prognostic biomarkers, particularly when integrated with HRD stratification. The expression of specific GI-lncRNAs was associated with primary therapy response and immune infiltration in LUAD. Additionally, we identified existing drugs that could modulate GI-lncRNAs, offering potential therapeutic strategies to address GI in LUAD. Conclusions: Our findings suggest that GI-associated lncRNAs could serve as valuable biomarkers for LUAD prognosis and therapeutic response. Furthermore, modulating these lncRNAs presents potential treatment avenues to address genomic instability in LUAD. Full article
(This article belongs to the Special Issue New and Emerging Strategies for Targeting Genomic Instability and Overcoming Drug Resistance in Lung Cancer)
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Review

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36 pages, 1476 KiB  
Review
Targeting Kinesins for Therapeutic Exploitation of Chromosomal Instability in Lung Cancer
by Christopher Zhang, Benson Z. Wu and Kelsie L. Thu
Cancers 2025, 17(4), 685; https://doi.org/10.3390/cancers17040685 - 18 Feb 2025
Viewed by 725
Abstract
New therapeutic approaches that antagonize tumour-promoting phenotypes in lung cancer are needed to improve patient outcomes. Chromosomal instability (CIN) is a hallmark of lung cancer characterized by the ongoing acquisition of genetic alterations that include the gain and loss of whole chromosomes or [...] Read more.
New therapeutic approaches that antagonize tumour-promoting phenotypes in lung cancer are needed to improve patient outcomes. Chromosomal instability (CIN) is a hallmark of lung cancer characterized by the ongoing acquisition of genetic alterations that include the gain and loss of whole chromosomes or segments of chromosomes as well as chromosomal rearrangements during cell division. Although it provides genetic diversity that fuels tumour evolution and enables the acquisition of aggressive phenotypes like immune evasion, metastasis, and drug resistance, too much CIN can be lethal because it creates genetic imbalances that disrupt essential genes and induce severe proteotoxic and metabolic stress. As such, sustaining advantageous levels of CIN that are compatible with survival is a fine balance in cancer cells, and potentiating CIN to levels that exceed a tolerable threshold is a promising treatment strategy for inherently unstable tumours like lung cancer. Kinesins are a superfamily of motor proteins with many members having functions in mitosis that are critical for the correct segregation of chromosomes and, consequently, maintaining genomic integrity. Accordingly, inhibition of such kinesins has been shown to exacerbate CIN. Therefore, inhibiting mitotic kinesins represents a promising strategy for amplifying CIN to lethal levels in vulnerable cancer cells. In this review, we describe the concept of CIN as a therapeutic vulnerability and comprehensively summarize studies reporting the clinical and functional relevance of kinesins in lung cancer, with the goal of outlining how kinesin inhibition, or “targeting kinesins”, holds great potential as an effective strategy for treating lung cancer. Full article
(This article belongs to the Special Issue New and Emerging Strategies for Targeting Genomic Instability and Overcoming Drug Resistance in Lung Cancer)
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22 pages, 1785 KiB  
Review
MET Activation in Lung Cancer and Response to Targeted Therapies
by Sarah Anna Okun, Daniel Lu, Katherine Sew, Asha Subramaniam and William W. Lockwood
Cancers 2025, 17(2), 281; https://doi.org/10.3390/cancers17020281 - 16 Jan 2025
Viewed by 1912
Abstract
The hepatocyte growth factor receptor (MET) is a receptor tyrosine kinase (RTK) that mediates the activity of a variety of downstream pathways upon its activation. These pathways regulate various physiological processes within the cell, including growth, survival, proliferation, and motility. Under normal physiological [...] Read more.
The hepatocyte growth factor receptor (MET) is a receptor tyrosine kinase (RTK) that mediates the activity of a variety of downstream pathways upon its activation. These pathways regulate various physiological processes within the cell, including growth, survival, proliferation, and motility. Under normal physiological conditions, this allows MET to regulate various development and regenerative processes; however, mutations resulting in aberrant MET activity and the consequent dysregulation of downstream signaling can contribute to cellular pathophysiology. Mutations within MET have been identified in a variety of cancers and have been shown to mediate tumorigenesis by increasing RTK activity and downstream signaling. In lung cancer specifically, a number of patients have been identified as possessing MET alterations, commonly receptor amplification (METamp) or splice site mutations resulting in loss of exon 14 (METex14). Due to MET’s role in mediating oncogenesis, it has become an attractive clinical target and has led to the development of various targeted therapies, including MET tyrosine kinase inhibitors (TKIs). Unfortunately, these TKIs have demonstrated limited clinical efficacy, as patients often present with either primary or acquired resistance to these therapies. Mechanisms of resistance vary but often occur through off-target or bypass mechanisms that render downstream signaling pathways insensitive to MET inhibition. This review provides an overview of the therapeutic landscape for MET-positive cancers and explores the various mechanisms that contribute to therapeutic resistance in these cases. Full article
(This article belongs to the Special Issue New and Emerging Strategies for Targeting Genomic Instability and Overcoming Drug Resistance in Lung Cancer)
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24 pages, 1665 KiB  
Review
Neuroendocrine Transformation as a Mechanism of Resistance to Targeted Lung Cancer Therapies: Emerging Mechanisms and Their Therapeutic Implications
by Asim Joshi, Nivitha Bhaskar and Joel D. Pearson
Cancers 2025, 17(2), 260; https://doi.org/10.3390/cancers17020260 - 15 Jan 2025
Viewed by 1371
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide, highlighting a major clinical challenge. Lung cancer is broadly classified into two histologically distinct subtypes, termed small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). Identification of various oncogenic drivers of [...] Read more.
Lung cancer is the leading cause of cancer-related deaths worldwide, highlighting a major clinical challenge. Lung cancer is broadly classified into two histologically distinct subtypes, termed small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). Identification of various oncogenic drivers of NSCLC has facilitated the development of targeted therapies that have dramatically improved patient outcomes. However, acquired resistance to these targeted therapies is common, which ultimately results in patient relapse. Several on-target and off-target resistance mechanisms have been described for targeted therapies in NSCLC. One common off-target mechanism of resistance to these therapies is histological transformation of the initial NSCLC into SCLC, a highly aggressive form of lung cancer that exhibits neuroendocrine histology. This mechanism of resistance presents a significant clinical challenge, since there are very few treatments available for these relapsed patients. Although the phenomenon of NSCLC-to-SCLC transformation was described almost 20 years ago, only recently have we begun to understand the mechanisms underlying this therapy-driven response. These recent discoveries will be key to identifying novel biomarkers and therapeutic strategies to improve outcomes of patients that undergo NSCLC-to-SCLC transformation. Here, we highlight these recent advances and discuss the potential therapeutic strategies that they have uncovered to target this mechanism of resistance. Full article
(This article belongs to the Special Issue New and Emerging Strategies for Targeting Genomic Instability and Overcoming Drug Resistance in Lung Cancer)
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33 pages, 1547 KiB  
Review
Strategies to Target Chemoradiotherapy Resistance in Small Cell Lung Cancer
by Tony Yu and Benjamin H. Lok
Cancers 2024, 16(20), 3438; https://doi.org/10.3390/cancers16203438 - 10 Oct 2024
Viewed by 2067
Abstract
Background: Small cell lung cancer (SCLC) is a lethal form of lung cancer with few treatment options and a high rate of relapse. While SCLC is initially sensitive to first-line DNA-damaging chemo- and radiotherapy, relapse disease is almost universally therapy-resistant. As a result, [...] Read more.
Background: Small cell lung cancer (SCLC) is a lethal form of lung cancer with few treatment options and a high rate of relapse. While SCLC is initially sensitive to first-line DNA-damaging chemo- and radiotherapy, relapse disease is almost universally therapy-resistant. As a result, there has been interest in understanding the mechanisms of therapeutic resistance in this disease. Conclusions: Progress has been made in elucidating these mechanisms, particularly as they relate to the DNA damage response and SCLC differentiation and transformation, leading to many clinical trials investigating new therapies and combinations. Yet there remain many gaps in our understanding, such as the effect of epigenetics or the tumor microenvironment on treatment response, and no single mechanism has been found to be ubiquitous, suggesting a significant heterogeneity in the mechanisms of acquired resistance. Nevertheless, the advancement of techniques in the laboratory and the clinic will improve our ability to study this disease, especially in patient populations, and identify methods to surmount therapeutic resistance. Full article
(This article belongs to the Special Issue New and Emerging Strategies for Targeting Genomic Instability and Overcoming Drug Resistance in Lung Cancer)
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