Cancer Science最新文献

Despite advances in androgen receptor signaling inhibitors (ARSIs) and poly (ADP-ribose) polymerase inhibitors (PARPIs), metastatic castration-resistant prostate cancer (mCRPC) remains lethal. PARPIs clinical efficacy is limited in patients with homologous recombination repair deficiencies, such as BRCA1/2 mutations, due to resistance. Thus, identifying novel synthetic lethal interactions with PARP may expand treatment options and improve therapeutic efficacy. Here, to identify genes that influence sensitivity to the PARPI olaparib, we conducted a genome-wide CRISPR-Cas9 knockout screening of 18,010 genes in DU145, 22Rv1, and LNCaP prostate cancer cell lines. Our screening identified PARP and LIG1 as synthetic lethality-inducing factors, whereas TP53 conferred resistance to PARPIs. Simultaneous inhibition of LIG1 and PARP increased DNA damage and apoptosis. Additionally, the combination of the LIG1 inhibitor L82-G17 with olaparib exhibited synergistic effects. To the best of our knowledge, we validated this combination therapy in vivo for the first time, suppressing tumor growth in a DU145 xenograft model while minimizing toxicity in normal tissues. Immunohistochemical analysis revealed that LIG1 was overexpressed in CRPC tissues, suggesting its potential as a therapeutic target. This study established LIG1 as a novel synthetic lethality-inducing factor in prostate cancer, showing that L82-G17 enhances the efficacy of olaparib, regardless of the BRCA mutation status. These findings suggest that the combination of PARP and LIG1 inhibitors could be a novel therapeutic strategy for mCRPC.

Tumor metastasis remains a poor prognosis because it occurs in all tissues and is difficult to diagnose or prevent before metastatic tumor nodules form. Metastasis is a multi-step process involving tumor cells, bone marrow-derived cells, and tissue resident cells, making it a biological three-body problem. It has been shown that a pre-metastatic soil/niche (PMN) is formed in metastatic tissue before tumor cells physically appear at the metastatic site, and suppressing this PMN is key to preventing metastasis. Recent studies highlighted the importance of protein citrullination, an irreversible post-translational modification of proteins, in tumor metastasis. Peptidyl arginine deiminase (PADI) catalyzes the modification of arginine to citrulline. In this enzymatic reaction, the amino acid residue's net charge changes, inducing a structural change in the protein. This review discusses the role of protein citrullination in cancer metastasis. Intracellular citrullination regulates gene expression and genome structure by citrullinating RNA polymerase and histones, while extracellular citrullination provides a pro-metastatic environment. These factors play an important role in PMN formation. Additionally, we discuss PADI inhibitors and anti-metastatic immune cells from the viewpoint of metastasis prevention.

Cancer treatment is shifting from an organ-based approach to one driven by biological phenotypes, emphasizing the need to understand molecular mechanisms. DNA methylation plays a pivotal role in tumor biology, not only through gene silencing but also by inducing distinct behaviors beyond genetic mutations. In gynecologic cancers, molecular diagnostics, such as homologous recombination deficiency status guiding poly(ADP-ribose) polymerase (PARP) inhibitor therapy in ovarian cancer and deficient mismatch repair/microsatellite instability-high status informing immune checkpoint inhibitor (ICI) therapy in endometrial cancer have already been used in clinical practice. However, tumors with epigenetically driven functional deficiencies, such as BRCA1 promoter methylation in homologous recombination-deficient ovarian cancers or MLH1 promoter methylation in deficient mismatch repair/microsatellite instability-high endometrial cancers, often exhibit poorer prognoses and reduced therapeutic responses compared to their genetically mutated counterparts. Given the unique impact of DNA methylation, precise detection is crucial. Integrating methylation analysis into molecular classification could refine diagnostics—both by identifying mechanistic contributors to treatment response and by serving as predictive biomarkers for therapy selection—thereby optimizing patient management. This review explores the role of DNA methylation in modulating responses to PARP inhibitors and ICIs, highlights its promise as a biomarker in precision oncology, and outlines current developments and clinical challenges in BRCA1 and MLH1 methylation assays.

Accumulating data demonstrate the robust overall and intracranial activity of trastuzumab deruxtecan (T-DXd) in HER2-positive breast cancer brain metastasis (BCBM). Limited data are available on HER2-low/zero BCBM, as well as patients with symptomatic active BM, leptomeningeal disease (LMD), and poor performance status. This multicenter, retrospective, real-world study enrolled patients diagnosed with HER2-positive or low/zero BCBM receiving T-DXd. Progression-free survival (PFS), intracranial progression-free survival (IC-PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), IC-ORR, IC-DCR, and adverse events (AEs) were evaluated. From January 2020 to July 2024, 58 HER2-positive and 30 HER2-low/zero patients were enrolled. In the HER2-positive cohort, the median PFS, IC-PFS, and OS were 11, 13, and 46 months, respectively. ORR and DCR were 65.2% and 91.3% systemically, with IC-ORR and IC-DCR of 61.0%/90.2% (RECIST 1.1) and 59.5%/88.1% (RANO-BM). In the HER2-low/zero cohort, median PFS, IC-PFS, and OS were 4, 5, and 26 months. ORR and DCR were 33.3% and 66.7%. IC-ORR and IC-DCR were 44.4% and 88.9% by RECIST 1.1 and RANO-BM. HR+/HER2-low patients had significantly longer PFS than HR-/HER2-low (10 vs. 3 months, p < 0.001). In the LMD cohort, the 12-month IC-PFS rates were 67.7% and 60.0% in HER2-positive and low/zero cohorts. The most common AEs included fatigue (45.9%) and appetite loss (25.2%). Seven (8.0%) patients suffered interstitial lung disease (ILD), including 2 (2.3%) grade 3. T-DXd showed substantial and durable overall and intracranial efficacy in HER2-positive and low/zero BCBM, including challenging subgroups with active BM or LMD.

Low-density lipoprotein receptor-related protein 11 (LRP11) is reported to be overexpressed in various cancers; however, its functional role in lung adenocarcinoma remains poorly understood. This study aimed to elucidate the tumor-promoting function of LRP11 in lung adenocarcinoma. We assessed the expression and function of LRP11 in lung adenocarcinoma cell lines through both silencing and overexpression experiments. RNA sequencing was performed to identify genes associated with LRP11 expression. The clinical relevance was evaluated using public datasets (The Cancer Genome Atlas and the Singapore Oncology Data Portal). LRP11 was overexpressed in lung adenocarcinoma cells and promoted their proliferation in vitro. RNA sequencing identified multiple genes negatively correlated with LRP11, all of which contained predicted C/EBPβ binding motifs in their promoter regions. Clinically, high LRP11 expression was associated with poor prognosis in patients with lung adenocarcinoma. In conclusion, LRP11 promotes lung adenocarcinoma progression by enhancing cell proliferation and modulating transcriptional activity. These findings suggest that LRP11 may serve as a potential therapeutic target and prognostic biomarker in lung adenocarcinoma.

Despite recent advances in neoadjuvant strategies for locally advanced rectal cancer (LARC), optimal chemotherapy regimens and the role of genetic biomarkers in guiding treatment remain unclear. Moreover, predictive markers are urgently needed for radiation-sparing strategies. Therefore, we aimed to assess the predictive and prognostic value of TP53, KRAS, and APC mutations in patients with LARC undergoing neoadjuvant chemotherapy (NACT) by retrospectively analyzing 43 patients with LARC who underwent NACT without radiation. Treatment response was assessed using RECIST criteria, revealing that 55.8% of patients exhibited a complete or partial response, which was significantly correlated with improved recurrence-free survival (p = 0.015). Conversely, tumor regression grade (TRG) did not predict survival outcomes. Targeted amplicon sequencing of pre-treatment biopsy and surgical specimens revealed high mutation frequencies in TP53 (74.4%), KRAS (44.1%), and APC (32.5%). TP53 mutations included diverse alterations, particularly gain-of-function missense variants, reflected in distinct immunohistochemical patterns. KRAS mutations mainly affected codon 12, and APC mutations were predominantly truncating. Notably, KRAS + APC co-mutations, observed in 11.6% of patients, were significantly associated with poor overall survival (p = 0.046), suggesting a synergistic role in poor prognosis. Conversely, patients with TP53 mutations exhibited improved survival (p = 0.007), underscoring their potential as favorable prognostic markers. Therefore, specific genetic alterations influence both prognosis and response to chemotherapy, offering critical insights into personalized treatment planning. Incorporating comprehensive molecular profiling—particularly TP53, KRAS, and APC mutation status—for preoperative evaluation may refine risk stratification, inform surgical decision-making, and support tailored therapeutic approaches in LARC.

Polyploid giant cancer cells (PGCCs) represent a unique and distinct subset of cancer cells, characterized by either an abnormally large nucleus or the presence of multiple nuclei within a single cell. An increasing body of evidence indicates that PGCCs are closely linked to cancer progression, therapeutic resistance, and poor clinical prognosis. However, despite their distinctive morphology, no universal marker has been identified to reliably distinguish PGCCs from other cancer cell populations. This is at least partly because PGCCs arise across various cancer types in diverse contexts, displaying considerable variability in their gene expression profiles. Nevertheless, they share key features, most notably polyploidy and remarkable stress resilience. The exceptional stress resilience of PGCCs arises from various mechanisms, including genome redundancy buffering against genetic damage, dormancy induction for survival in harsh conditions, gene expression changes enhancing hypoxia resistance, and metabolic adaptations supporting growth in resource-limited environments. Collectively, these properties make PGCCs highly resilient to stress, facilitating their persistence and contributing to the progression and aggressiveness of cancer. In this review, we provide a comprehensive discussion of the mechanisms underlying PGCC stress resilience and explore its broader implications for cancer pathogenesis. Understanding these adaptive strategies may offer new insights into cancer biology and reveal potential therapeutic targets to mitigate PGCC-driven malignancy.

Epidermal growth factor receptor (EGFR) exon 20 insertion mutations (EGFR Exon 20ins) are the third most common mutations in non-small cell lung cancer (NSCLC) and are associated with a poorer prognosis and resistance to conventional EGFR-tyrosine kinase inhibitors. This subpopulation analysis of the open-label phase 3 trial (PAPILLION) evaluates the efficacy and safety of amivantamab–chemotherapy versus chemotherapy among Japanese patients with locally advanced or metastatic NSCLC with EGFR Exon 20ins mutation (ClinicalTrials.gov, NCT04538664). Patients were randomized 1:1 to either intravenous amivantamab plus carboplatin/pemetrexed chemotherapy or chemotherapy alone. The primary endpoint was progression-free survival (PFS) by blinded independent central review; the secondary endpoints included objective response rate, duration of response, PFS after first subsequent therapy, overall survival, and safety. The overall population (n = 308) included 34 Japanese patients (amivantamab–chemotherapy, n = 19; chemotherapy, n = 15). Median PFS was 15.5 (95% CI 8.0, NE) months with amivantamab–chemotherapy compared with 5.6 (95% CI 3.0, 7.0) months (HR = 0.22 [0.09, 0.53]) for chemotherapy alone. Improvements in secondary endpoints were also greater in the amivantamab–chemotherapy arm than the chemotherapy arm. The predominant adverse events associated with amivantamab–chemotherapy were reversible hematologic and EGFR-related toxic effects; 2 of 19 patients discontinued all study agents due to treatment-emergent adverse events. Efficacy and safety results in this Japanese subpopulation were consistent with those in the overall population and support the first-line use of amivantamab–chemotherapy in this setting. Early identification of patients with EGFR Exon 20ins mutations, preferably with more sensitive next-generation sequencing-based methods, is important to ensure appropriate patient access to amivantamab–chemotherapy.

Trial Registration: ClinicalTrials.gov, NCT04538664.

Histone H3K4 modifications are altered in the regulation of gene expression and in multiple cellular processes during cancer development and progression. Understanding the roles of H3K4-modifying enzymes will provide novel insights into therapeutic tools for cancer treatment. H3K4-modifying enzymes catalyze the addition or removal of covalent modifications with specific substrate preferences. Although these proteins are evolutionarily conserved between yeast and mammals, their protein domains and functions are not identical, and they exhibit signs of evolutionary divergence. Recent studies have indicated that H3K4-modifying enzymes play non-canonical roles via non-histone substrates or non-catalytic functions. Here, we discuss both canonical and non-canonical functions of H3K4-modifying enzymes and their potential benefits for therapeutic applications in cancer therapy.

Cancer risk increases with age, and cellular senescence may be a major contributor to cellular carcinogenesis. Enormous efforts have been made to investigate the interrelation between aging and tumors, but little is known about the comparative features of normal aging, cellular senescence, and cancer at single-cell resolution. By integrating analyses of genomics, epigenomics, and bulk and single-cell transcriptomics, we revealed a directionally opposite transcriptional profile between cellular senescence and tumorigenesis at the single-cell level, which may be affected by epigenomic regulations. A total of 648 aging-dependent senescence-associated coregulated modules (SACMs), disproportionately affecting the reproductive systems of both females and males, were initially defined across 17 tissues. Single-cell analysis revealed that aging primarily affects endothelial cells, followed by T cells, epithelial cells, macrophages, and fibroblasts. Opposite directions of change in gene expression between aging and cancer can commonly be observed in endothelial, fibroblast, and epithelial cells, which may prompt the opposing patterns of gene expression between tissue aging and epithelial carcinoma at the bulk level. A similar pattern of expression can be observed in immune cells, which are characterized by decreased self-renewal with aging, but this pattern is reversed in epithelial carcinoma. Our study highlighted the role of senescence as a natural barrier against tumor formation and supported the idea that aging-related systemic environment changes create a protumorigenic milieu.