Mechanisms Of Resistance In Cancer Research Articles

Breathing down resistance: Tackling hypoxia to overcome immunotherapy barriers in lung cancer.

In this issue of JEM, Robles-Oteiza et al. (https://doi.org/10.1084/jem.20231106) present compelling evidence linking tumor hypoxia to acquired resistance mechanisms in non-small cell lung cancer (NSCLC) treatments involving immune checkpoint inhibitors (ICIs). Their research advocates targeting these hypoxic tumor regions with hypoxia-activated pro-drugs like TH-302, which may substantially delay the onset of resistance and herald a significant advancement in cancer therapy.

Mechanisms of endocrine resistance in hormone receptor-positive breast cancer.

Hormone receptor-positive breast cancer may recur or metastasize years or decades after its diagnosis. Furthermore, hormone receptor expression may persist in relapsed or metastatic cancer cells. Endocrine therapy is one of the most efficacious treatments for hormone receptor-positive breast cancers. Nevertheless, a considerable proportion of patients develop resistance to endocrine therapy. Previous studies have identified numerous mechanisms underlying drug resistance, such as epigenetic abnormalities in the estrogen receptor (ER) genome, activation of ER-independent ligands, and alterations in signaling pathways including PI3K/AKT/mTOR, Notch, NF-κB, FGFR, and IRE1-XBP1. This article reviews the mechanisms of endocrine resistance in hormone receptor-positive advanced breast cancer, drawing from previous studies, and discusses the latest research advancements and prospects.

Novel Perspectives in the Management of Colorectal Cancer: Mechanistic Investigations Into the Reversal of Drug Resistance via Active Constituents Derived From Herbal Medicine.

The high incidence and mortality rate of colorectal cancer have become a significant global health burden. Chemotherapy has been the traditional treatment for colorectal cancer and has demonstrated promising antitumor effects, leading to significant improvements in patient survival. However, the development of chemoresistance poses a major challenge during chemotherapy in colorectal cancer, significantly impeding treatment efficacy and affecting patient prognosis. Despite the development of a variety of novel anticolorectal cancer chemotherapy agents, their effectiveness and side effects vary, possibly due to the complex mechanisms of resistance in colorectal cancer. Abnormal drug metabolism or protein targets are the most direct causes of resistance. Further studies have revealed that these resistance mechanisms involve biochemical processes such as altered protein expression, autophagy, and epithelial-mesenchymal transitions. Herbal active ingredients offer an alternative treatment option and have shown promise in reversing colorectal cancer drug resistance. This paper aims to summarize the role of various biochemical processes and key protein targets in the occurrence and maintenance of resistance mechanisms in colorectal cancer. Additionally, it elaborates on the mechanisms of action of herbal active ingredients in reversing colorectal cancer drug resistance. The article also discusses the limitations and opportunities in developing novel anticolorectal cancer drugs based on herbal medicine.

Cancer Prevalence across Vertebrates.

Cancer is pervasive across multicellular species, but what explains the differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades of tetrapods (amphibians, sauropsids, and mammals), we found that neoplasia and malignancy prevalence increases with adult mass (contrary to Peto's paradox) and somatic mutation rate but decreases with gestation time. The relationship between adult mass and malignancy prevalence was only apparent when we controlled for gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%), the black-footed penguin (<0.4%), ferrets (63%), and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer. Significance: Evolution has discovered mechanisms for suppressing cancer in a wide variety of species. By analyzing veterinary necropsy records, we can identify species with exceptionally high or low cancer prevalence. Discovering the mechanisms of cancer susceptibility and resistance may help improve cancer prevention and explain cancer syndromes.

The interaction between UBR7 and PRMT5 drives PDAC resistance to gemcitabine by regulating glycolysis and immune microenvironment

Pancreatic ductal adenocarcinoma (PDAC) is a common malignant tumor of the digestive tract. Although gemcitabine and other therapeutic agents are effective in patients with advanced and metastatic pancreatic cancer, drug resistance has severely limited their use. However, the mechanisms of gemcitabine resistance in pancreatic cancer are poorly understood. In this study, ATAC-seq, ChIP-seq, and RNA-seq were performed to compare chromatin accessibility and gene expression in a patient-derived tumor xenograft (PDX) model of pancreatic cancer with or without gemcitabine resistance. Analyzing these sequencing data, we found a dramatic change in chromatin accessibility in the PDX model of gemcitabine-resistant tissues and identified a key gene, UBR7, which plays an important role in mediating gemcitabine resistance. Further research found that depletion of UBR7 significantly increased pancreatic carcinogenesis and the immunosuppressive microenvironment. Mechanistically, depleted UBR7 increased the stability of PRMT5, thereby promoting glycolysis in pancreatic cancer cells. Finally, an inhibitor that blocks PRMT5 (DS-437) significantly reduced gemcitabine resistance in pancreatic cancer caused by UBR7 depletion. In conclusion, our results illustrate that the UBR7-PRMT5 axis is a key metabolic regulator of PDAC and a promising target for the clinical treatment of gemcitabine resistance in PDAC.

Proteolysis Targeting Chimera Agents (PROTACs): New Hope for Overcoming the Resistance Mechanisms in Oncogene-Addicted Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) remains a disease with a poor prognosis despite the advances in therapies. NSCLC with actionable oncogenic alterations represent a subgroup of diseases for which tyrosine kinase inhibitors (TKIs) have shown relevant and robust impact on prognosis, both in early and advanced stages. While the introduction of powerful TKIs increases the ratio of potentially curable patients, the disease does develop resistance over time through either secondary mutations or bypass activating tracks. Therefore, new treatment strategies are being developed to either overcome this inevitable resistance or to prevent it, and proteolysis targeting chimera agents (PROTACs) are among them. They consist of two linked molecules that bind to a target protein and an E3 ubiquitin ligase that causes ubiquitination and degradation of proteins of interest. In this paper, we review the rationale for PROTAC therapy and the current development of PROTACs for oncogene-addicted lung cancer. Moreover, we critically analyze the strengths and limitations of this promising technique that may help pave the way for future perspectives.

7831 Unveiling Drug Resistance Mechanisms in Triple-Positive Breast Cancer: Insights from Long-Term Estrogen Deprivation Models and Innovative Mutation Detection Strategies

Abstract Disclosure: S. Bahnassy: None. H.S. Andrews: None. L. Jin: None. B.F. Kohrn: None. S. Tam: None. D. Mobin: None. Y.J. Dunn: None. M. Balachandran: None. M. Podar: None. W. He: None. M.D. McCoy: None. R.A. Beckman: Consulting Fee; Self; AstraZeneca, Boehringer Ingelheim. Other; Self; Chief Scientific Officer of OncoMind, LLC, which owns patents on dynamic precision medicine. R.B. Riggins: None. Compelling evidence from preclinical and clinical data suggests that triple-positive (TP; HER2+/HR+) breast cancer (BC) has lower response rates to HER2-targeted therapy and a higher risk of recurrence to endocrine therapy (ET) than HER2+/HR−. Molecular mechanisms underpinning drug resistance in TP-BC are poorly understood, thereby limiting our ability to improve patient outcomes and prevent metastatic progression. In our recent publication, we established and characterized long-term estrogen deprivation (LTED) ET-resistant (ETR) TP-BC models that mimic resistance to aromatase inhibitors without using genetic manipulation approaches. We reported intrinsic subtype shifts towards non-luminal phenotypes, metabolic reprogramming, and acquiring mutations in genes encoding for transcription factors and chromatin modifiers, as potential mechanisms of ETR in our LTED models. The emergence of drug-resistant mutator subclones under treatment-induced selective pressures, coupled with limitations in shallow-depth whole genome sequencing coverage, highlight an unmet need to develop a strategy for visually monitoring, capturing, and mapping resistant subclones through a mutational phenotypic screen, an approach offering valuable insights for optimizing treatment schedules. To address this, we developed and applied an innovative dual fluorescence mutation detection system to detect mutator cells expressing both mCherry and green fluorescence protein (GFP). First, we validated if our system is working properly. Compared to parental cells, transduced BT-474 and MDA-MB-361 LTEDs showed a drastic increase in GFP+ cells, suggesting the presence of resistant mutator cells. Consistent with the increase in GFP signal, TP-LTEDs showed increased mutation number and frequency in two Duplex Sequencing targeted capture panels (neutral loci and DNA polymerase-focused), used to perform ultra-deep, highly accurate sequencing. We then treated parental cells with single, dual, and triple combinations of anti-HER2, ET and CDK4/6 inhibitors to track the emergence of GFP+ mutator cells. Nine-day treatments with triple combinatorial therapies were best at inhibiting the growth of both BT-474 and MDA-MB-361 parental cell lines, compared to single- and double-agent targeted therapies. However, no GFP signal was detected within treated cells, suggesting that longer treatment durations are needed for drug-resistance mutator subclones to be discovered. Ongoing studies monitoring TP-drug resistance mutator subclones with long-term conventional targeted-therapies will improve our understanding of drug resistance mechanisms in this understudied subtype of BC. Importantly, these studies will enable dynamic precision medicine simulations to empower for a more tailored and effective therapeutic administration to prevent drug resistance and metastatic progression of TP-BC. Presentation: 6/3/2024

Deciphering resistance mechanisms in cancer: final report of MATCH-R study with a focus on molecular drivers and PDX development

BackgroundUnderstanding the resistance mechanisms of tumor is crucial for advancing cancer therapies. The prospective MATCH-R trial (NCT02517892), led by Gustave Roussy, aimed to characterize resistance mechanisms to cancer treatments through molecular analysis of fresh tumor biopsies. This report presents the genomic data analysis of the MATCH-R study conducted from 2015 to 2022 and focuses on targeted therapies.MethodsThe study included resistant metastatic patients (pts) who accepted an image-guided tumor biopsy. After evaluation of tumor content (TC) in frozen tissue biopsies, targeted NGS (10 < TC < 30%) or Whole Exome Sequencing and RNA sequencing (TC > 30%) were performed before and/or after the anticancer therapy.Patient-derived xenografts (PDX) were established by implanting tumor fragments into NOD scid gamma mice and amplified up to five passages.ResultsA total of 1,120 biopsies were collected from 857 pts with the most frequent tumor types being lung (38.8%), digestive (16.3%) and prostate (14.1%) cancer. Molecular targetable driver were identified in 30.9% (n = 265/857) of the patients, with EGFR (41.5%), FGFR2/3 (15.5%), ALK (11.7%), BRAF (6.8%), and KRAS (5.7%) being the most common altered genes. Furthermore, 66.0% (n = 175/265) had a biopsy at progression on targeted therapy. Among resistant cases, 41.1% (n = 72/175) had no identified molecular mechanism, 32.0% (n = 56/175) showed on-target resistance, and 25.1% (n = 44/175) exhibited a by-pass resistance mechanism. Molecular profiling of the 44 patients with by-pass resistance identified 51 variants, with KRAS (13.7%), PIK3CA (11.8%), PTEN (11.8%), NF2 (7.8%), AKT1 (5.9%), and NF1 (5.9%) being the most altered genes. Treatment was tailored for 45% of the patients with a resistance mechanism identified leading to an 11 months median extension of clinical benefit.A total of 341 biopsies were implanted in mice, successfully establishing 136 PDX models achieving a 39.9% success rate. PDX models are available for EGFR (n = 31), FGFR2/3 (n = 26), KRAS (n = 18), ALK (n = 16), BRAF (n = 6) and NTRK (n = 2) driven cancers. These models closely recapitulate the biology of the original tumors in term of molecular alterations and pharmacological status, and served as valuable models to validate overcoming treatment strategies.ConclusionThe MATCH-R study highlights the feasibility of on purpose image guided tumor biopsies and PDX establishment to characterize resistance mechanisms and guide personalized therapies to improve outcomes in pre-treated metastatic patients.Graphical

Resistance to the platinum‑based chemotherapeutic drugs in oral cancer: Focus on the role of p22phox (Review).

Oral cancer, commonly known as oral squamous cell carcinoma (OSCC), is an aggressive malignancy in the oral cavity with a poor prognosis and survival rate, particularly at the advanced stages. Oral cancer represents one of the most widespread cancers worldwide, in which the prevalence is particularly high in South and Southeast Asia. While the incidence and mortality rates continue to increase over the past decades, oral cancer treatment can be challenging and at times ineffective, largely due to drug resistance. To date, platinum-based drugs, such as cisplatin, remain the mainstay of chemotherapy for patients with oral cancer. However, long-term exposure to cisplatin inevitably leads to the development of resistance to the drug, which is still a major issue to overcome in oral cancer treatment. The molecular mechanisms of cisplatin resistance in oral cancer have been extensively studied in recent years and the present review places specific emphasis on a novel mechanism of resistance to the platinum drugs mediated by p22phox, an endoplasmic reticulum membrane protein. In addition to delineating the unique p22phox-dependent cisplatin resistance, the present review compares and contrasts the resistance mechanism to its current counterparts. Finally, with the goal of tackling the problem of chemotherapy resistance in oral cancer, various strategies are presented that may counteract p22phox-dependent cisplatin resistance, which may potentially improve the efficacy of the platinum-based drugs and warrant future clinical validation.

422 (PB410): Understanding Mechanisms of Cancer Drug Sensitivity and Resistance Using Functional Genomic Approaches

422 (PB410): Understanding Mechanisms of Cancer Drug Sensitivity and Resistance Using Functional Genomic Approaches

Research into overcoming drug resistance in lung cancer treatment using CRISPR-Cas9 technology: a narrative review.

Lung cancer remains a leading cause of cancer-related mortality globally, with drug resistance posing a significant challenge to effective treatment. The advent of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (CRISPR-Cas9) technology offers a novel and precise gene-editing technology for targeting and negating drug resistance mechanisms in lung cancer. This review summarizes the research progress in the use of CRISPR-Cas9 technology for investigating and managing drug resistance in lung cancer treatment. A literature search was conducted using the Web of Science and PubMed databases, with the following keywords: [CRISPR-Cas9], [lung cancer], [drug resistance], [gene editing], and [gene therapy]. The search was limited to articles published in English from 2002 to September 2023. From the search results, studies that utilized CRISPR-Cas9 technology in the context of lung cancer drug resistance were selected for further analysis and summarize. CRISPR-Cas9 technology enables precise DNA-sequence editing, allowing for the targeted addition, deletion, or modification of genes. It has been applied to investigate drug resistance in lung cancer by focusing on key genes such as epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), tumor protein 53 (TP53), and B-cell lymphoma/leukemia-2 (BCL2), among others. The technology has shown potential in inhibiting tumor growth, repairing mutations, and enhancing the sensitivity of cancer cells to chemotherapy. Additionally, CRISPR-Cas9 has been used to identify novel key genes and molecular mechanisms contributing to drug resistance, offering new avenues for therapeutic intervention. The review also highlights the use of CRISPR-Cas9 in targeting immune escape mechanisms and the development of strategies to improve drug sensitivity. The CRISPR-Cas9 technology holds great promise for advancing lung cancer treatment, particularly in addressing drug resistance. The ability to precisely target and edit genes involved in resistance pathways offers a powerful tool for developing more effective and personalized therapies. While challenges remain in terms of delivery, safety, and ethical considerations, ongoing research and technological refinements are expected to further enhance the role of CRISPR-Cas9 in improving patient outcomes in lung cancer treatment.

Impact of Neuroendocrine Differentiation (NED) on Enzalutamide and Abiraterone Efficacy in Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Retrospective Analysis.

Neuroendocrine differentiation (NED) represents a possible androgen receptor pathway inhibitors (ARPI) resistance mechanism in metastatic castration resistance prostate cancer (mCRPC). As mCRPC with NED has been excluded from clinical trials evaluating ARPI efficacy, this study investigates the prognostic impact of NED in mCRPC patients treated with ARPIs. Methods: We retrospectively analyzed 327 mCRPC patient data treated with Enzalutamide or Abiraterone in the first and second or successive lines of treatment. NED was assessed using prostate biopsy samples through immunohistochemical staining. Results: NED was confirmed in 32/327 (9.8%) mCRPC patients. In the overall population, mCRPC with NED showed worse PFS (4.38 vs. 11.48 months HR 2.505 [1.71-3.68] p < 0.05), disease control rate (DCR), and PSA response. In the first line setting, mCRPC with NED demonstrated worse PFS (8.5 vs. 14.9 months HR 2.13 [1.18-3.88], p < 0.05). Similarly, in the second or successive lines, mCRPC with NED showed worse PFS (4.0 vs. 7.5 months HR 2.43 [1.45-4.05] p < 0.05), DCR, PSA response and OS (12.53 vs. 18.03 months HR 1.86 [1.12-3.10] p < 0.05). The adverse impact of NED on PFS was consistence across all subgroups; we also noted a trend of worse PFS in patients with high vs. low NED. Conclusions: In our study, mCRPC with NED treated with Enzalutamide or Abiraterone showed worse clinical outcomes. NED assessment should be considered to optimize treatment decisions in the mCRPC setting.

Loss of histone deubiquitinase Bap1 triggers anti-tumor immunity.

Immunotherapy using PD-L1 blockade is effective in only a small group of cancer patients, and resistance is common. This emphasizes the importance of understanding the mechanisms of cancer immune evasion and resistance. A genome-scale CRISPR-Cas9 screen identified Bap1 as a regulator of PD-L1 expression. To measure tumor size and survival, tumor cells were subcutaneously injected into both syngeneic WT mice and immunocompromised mice. The phenotypic and transcriptional characteristics of Bap1-deleted tumors were examined using flow cytometry, RNA-seq, and CUT&Tag-seq analysis. We found that loss of histone deubiquitinase Bap1 in cancer cells activates a cDC1-CD8+ T cell-dependent anti-tumor immunity. The absence of Bap1 leads to an increase in genes associated with anti-tumor immune response and a decrease in genes related to immune evasion. As a result, the tumor microenvironment becomes inflamed, with more cDC1 cells and effector CD8+ T cells, but fewer neutrophils and regulatory T cells. We also found that the elimination of Bap1-deleted tumors depends on the tumor MHCI molecule and Fas-mediated CD8+ T cell cytotoxicity. Our analysis of TCGA data further supports these findings, showing a reverse correlation between BAP1 expression and mRNA signatures of activated DCs and T-cell cytotoxicity in various human cancers. The histone deubiquitinase Bap1 could be used as a biomarker for tumor stratification and as a potential therapeutic target for cancer immunotherapies.

A bibliometric analysis of drug resistance in immunotherapy for breast cancer: trends, themes, and research focus.

While breast cancer treatments have advanced significantly nowadays, yet metastatic, especially triple-negative breast cancer (TNBC), remains challenging with low survival. Cancer immunotherapy, a promising approach for HER2-positive and TNBC, still faces resistance hurdles. Recently, numerous studies have set their sights on the resistance of immunotherapy for breast cancer. Our study provides a thorough comprehension of the current research landscape, hotspots, and emerging breakthroughs in this critical area through a meticulous bibliometric analysis. As of March 26, 2024, a total of 1341 articles on immunology resistance in breast cancer have been gathered from Web of Science Core Collection, including 765 articles and 576 reviews. Bibliometrix, CiteSpace and VOSviewer software were utilized to examine publications and citations per year, prolific countries, contributive institutions, high-level journals and scholars, as well as highly cited articles, references and keywords. The research of immunotherapy resistance in breast cancer has witnessed a remarkable surge over the past seven years. The United States and China have made significant contributions, with Harvard Medical School being the most prolific institution and actively engaging in collaborations. The most contributive author is Curigliano, G from the European Institute of Oncology in Italy, while Wucherpfennig, K. W. from the Dana-Farber Cancer Institute in the USA, had the highest citations. Journals highly productive primarily focus on clinical, immunology and oncology research. Common keywords include "resistance", "expression", "tumor microenvironment", "cancer", "T cell", "therapy", "chemotherapy" and "cell". Current research endeavors to unravel the mechanisms of immune resistance in breast cancer through theintegration of bioinformatics, basic experiments, and clinical trials. Efforts are underway to develop strategies that improve the effectiveness of immunotherapy, including the exploration of combination therapies and advancements in drug delivery systems. Additionally, there is a strong focus on identifying novel biomarkers that can predict patient response to immunology. This study will provide researchers with an up-to-date overview of the present knowledge in drug resistance of immunology for breast cancer, serving as a valuable resource for informed decision-making and further research on innovative approaches to address immunotherapy resistance.

Overcoming Cancer Resistance: Strategies and Modalities for Effective Treatment.

Resistance to cancer drugs is a complex phenomenon that poses a significant challenge in the treatment of various malignancies. This review comprehensively explores cancer resistance mechanisms and discusses emerging strategies and modalities to overcome this obstacle. Many factors contribute to cancer resistance, including genetic mutations, activation of alternative signaling pathways, and alterations in the tumor microenvironment. Innovative approaches, such as targeted protein degradation, immunotherapy combinations, precision medicine, and novel drug delivery systems, hold promise for improving treatment outcomes. Understanding the intricacies of cancer resistance and leveraging innovative modalities are essential for advancing cancer therapy.

PP01.93 RET fusion as a treatable resistance mechanism in EGFR mutation lung cancer - A case report

PP01.93 RET fusion as a treatable resistance mechanism in EGFR mutation lung cancer - A case report

Mechanisms of Drug Resistance in Breast Cancer

Breast cancer is a complex disease resulting from the interaction between genetic and environmental factors, and addressing them constitutes one of the major challenges in the treatment of this disease. Resistance to therapies represents a significant obstacle to achieving effective results in the treatment of breast cancer, multiple therapeutic approaches are available to address this disease in patients. The majority of breast cancer cases show estrogen receptor (ERα) expression, and treatments targeting this pathway are critical in their approach. However, the emergence of resistance to these treatments is a common problem, leading to cancer recurrence and relapse. This review provides an overview of the mechanisms contributing to drug resistance, highlighting the relevance of epigenetic factors as promising therapeutic targets to address clinical resistance. Furthermore, it emphasizes the importance of further research to find effective strategies that can overcome this resistance and improve treatment outcomes in patients suffering from breast cancer.

Hyaluronidase inhibitor delphinidin inhibits cancer metastasis

Cancer remains a formidable global health challenge, with metastasis being a key contributor to its lethality. Abundant high molecular mass hyaluronic acid, a major non-protein component of extracellular matrix, protects naked mole rats from cancer and reduces cancer incidence in mice. Hyaluronidase plays a critical role in degrading hyaluronic acid and is frequently overexpressed in metastatic cancer. Here we investigated the potential of targeting hyaluronidases to reduce metastasis. A high throughput screen identified delphinidin, a natural plant compound found in fruits and vegetables, as a potent hyaluronidase inhibitor. Delphinidin-mediated inhibition of hyaluronidase activity led to an increase in high molecular weight hyaluronic acid in cell culture and in mouse tissues, and reduced migration and invasion behavior of breast, prostate, and melanoma cancer cells. Moreover, delphinidin treatment suppressed melanoma metastasis in mice. Our study provides a proof of principle that inhibition of hyaluronidase activity suppresses cancer cell migration, invasion and metastasis. Furthermore, we identified a natural compound delphinidin as a potential anticancer therapeutic. Thus, we have identified a path for clinical translation of the cancer resistance mechanism identified in the naked mole rat.

Irinotecan Resistance Mechanisms in Cancer: Challenges and Opportunities

Irinotecan, a topoisomerase I inhibitor, has been widely used in the treatment of various solid tumors, including colorectal, lung, and pancreatic cancers. However, its efficacy is often limited by the development of resistance mechanisms within cancer cells. Understanding these resistance mechanisms is crucial for improving treatment outcomes and developing effective therapeutic strategies. This review article provides a comprehensive overview of the mechanisms underlying irinotecan resistance in cancer. Key resistance mechanisms discussed include the overexpression of drug efflux pumps, activation of DNA repair pathways, altered drug metabolism, and microenvironmental factors. Clinical implications, challenges, and emerging opportunities in overcoming irinotecan resistance are also explored, including the identification of biomarkers predictive of response/resistance, combination therapies targeting multiple resistance pathways, and advancements in drug delivery systems. By elucidating the complexities of irinotecan resistance, this review aims to inform future research directions and facilitate the development of personalized treatment approaches for patients with resistant cancers.

Extracellular Vesicle- and Mitochondria-Based Targeting of Non-Small Cell Lung Cancer Response to Radiation: Challenges and Perspectives.

During the cell life cycle, extracellular vesicles (EVs) transport different cargos, including organelles, proteins, RNAs, DNAs, metabolites, etc., that influence cell proliferation and apoptosis in recipient cells. EVs from metastatic cancer cells remodel the extracellular matrix and cells of the tumor microenvironment (TME), promoting tumor invasion and metastatic niche preparation. Although the process is not fully understood, evidence suggests that EVs facilitate genetic material transfer between cells. In the context of NSCLC, EVs can mediate intercellular mitochondrial (Mt) transfer, delivering mitochondria organelle (MtO), mitochondrial DNA (mtDNA), and/or mtRNA/proteinaceous cargo signatures (MtS) through different mechanisms. On the other hand, certain populations of cancer cells can hijack the MtO from TME cells mainly by using tunneling nanotubes (TNTs). This transfer aids in restoring mitochondrial function, benefiting benign cells with impaired metabolism and enabling restoration of their metabolic activity. However, the impact of transferring mitochondria versus transplanting intact mitochondrial organelles in cancer remains uncertain and the subject of debate. Some studies suggest that EV-mediated mitochondria delivery to cancer cells can impact how cancer responds to radiation. It might make the cancer more resistant or more sensitive to radiation. In our review, we aimed to point out the current controversy surrounding experimental data and to highlight new paradigm-shifting modalities in radiation therapy that could potentially overcome cancer resistance mechanisms in NSCLC.