Molecular Oncology最新文献

Excised signal circles (ESC) are circular DNA molecules generated during T- and B-cell maturation. Previously considered biologically inert, recent work by Gao et al. now show that ESCs can replicate and accumulate in healthy lymphocytes. Moreover, the authors link higher levels of ESCs to an increased risk of relapse in B-cell leukemia patients and propose that this phenomenon is due to the unique ability of ESCs to induce genome instability.

Erb-b2 receptor tyrosine kinase 2 (ERBB2; also known as HER2) expression is observed in 25-40% of head and neck squamous cell carcinomas (HNSCC), yet there are no anti-HER2 therapies under evaluation for HNSCC, as conventional cytostatic anti-HER2 antibodies have had limited effectiveness and levels of HER2 overexpression are lower in HNSCC tumors compared to breast cancer. Trastuzumab-deruxtecan (T-DXd; Enhertu) is a HER2-targeting antibody-drug conjugate (ADC) comprising an anti-HER2 monoclonal antibody, a cleavable linker, and a potent topoisomerase I inhibitor payload, and has shown promising results in very low HER2-expressing tumors. We compare the efficacy of T-DXd, trastuzumab-emtansine (ADC comprising an anti-HER2 antibody and microtubule inhibitor, T-DM1; Kadcyla) and trastuzumab (Herceptin) therapy in HNSCC with low and absent HER2 expression in vitro and in vivo. In vitro treatment of a low HER2-expressing human HNSCC cell line (FaDu) with T-DXd resulted in dose-dependent cell death (IC50 values of 9856 ng·mL^-1). T-DXd treatment of FaDu and UMSCC-47 (low HER2-expressing cell line) mouse xenografts displayed antitumor activity (P = 0.0001 and 0.015 respectively). When comparing T-DXd to other approved anti-HER2 therapies, only FaDu mice treated with T-DXd showed a reduction in tumor growth (P = 0.0012). In UMSCC-1 cells (absent HER2 expression), the drug failed to accumulate in tumors and showed no measurable antitumor effect, in contrast to FaDu xenografts, where drug accumulation in the tumor correlated with a therapeutic response. T-DXd treatment yielded antitumor activity in FaDu and UMSCC-47 tumors, highlighting the potential for T-DXd efficacy in low HER2-expressing tumors.

Bone morphogenetic protein (BMP) antagonists have been increasingly linked to the development of colorectal cancer (CRC). BMP signalling operates in opposition to the WNT signalling pathway, which sustains stem-cell maintenance and self-renewal of the normal intestinal epithelium. Reduced BMP and elevated WNT signalling lead to expansion of the stem-cell compartment and the hyperproliferation of epithelial cells, a defining characteristic of CRC. Chordin-like-2 (CHRDL2) is a secreted BMP antagonist, with overexpression linked to poor prognosis and variants in the gene shown to be associated with an elevated CRC risk. However, the detailed mechanism by which CHRDL2 contributes to CRC is unknown. In this study, we explored the impact of CHRDL2 overexpression on CRC cells to investigate whether CHRDL2's inhibition of BMP signalling intensifies WNT signalling and enhances the cancer stem-cell phenotype and response to treatment. Our research approach combines 2D cancer cell lines engineered to inducibly overexpress CHRDL2 and 3D organoid models treated with extrinsic CHRDL2, complemented by RNA sequencing analysis. CHRDL2 was found to enhance the survival of organoids and CRC cells during chemotherapy and irradiation treatment due to activation of DNA damage response pathways. Organoids treated with secreted CHRDL2 exhibited elevated levels of stem-cell markers and reduced differentiation, as evidenced by diminished villi budding. RNA-seq analysis revealed that CHRDL2 increased the expression of stem-cell markers, WNT signalling and other well-established cancer-associated pathways through BMP inhibition. These findings collectively suggest that CHRDL2 overexpression could affect response to CRC therapy by enhancing DNA repair and the stem-cell potential of cancer cells, and its role as a biomarker should be further explored.

Metastatic prostate cancer is incurable, and new therapeutic targets and drugs are urgently needed. Viral infections are associated with several cancer types, but a link between viruses and prostate oncogenesis has not been established. Only recently, an association between human cytomegalovirus (CMV) seropositivity and increased risk of prostate cancer mortality was demonstrated. Here, we show that CMV infection is common in the normal prostate epithelium and in prostate tumor tissue, with 70-92% of tumors being infected. Additionally, we report that commonly studied prostate cancer cell lines are CMV infected. Loss-of-function experiments demonstrate that CMV promotes cell survival, proliferation, and androgen receptor signaling, identifying it as a therapeutic target in castration-sensitive and castration-resistant prostate cancer. Several anti-CMV pharmaceutical compounds in clinical use inhibited cell expansion in prostate cancer models both in vitro and in vivo. We conclude that CMV is common in prostate cancer, promotes core prostate cancer cell programs, and can be inhibited by well-tolerated drugs. These findings motivate investigation into potential clinical benefits of CMV inhibition in the treatment of prostate cancer.

Clinical outcomes in ROS1-fusion positive (ROS1+) non-small cell lung cancer (NSCLC) by fusion partner and resistance mechanisms are limited. This cohort study included 56 ROS1+ patients (FISH or NGS confirmed); fusion partners were identified in 27 cases, including CD74 (n = 10), EZR (n = 7), and SDC4 (n = 7). Clinical data were available for 50 patients (median age 62; 51% female; 32% never-smokers). Forty patients received tyrosine kinase inhibitors (TKIs), mostly crizotinib (n = 38). Crizotinib showed a 55% objective response rate (ORR) and a median progression-free survival (mPFS) of 5.3 months. Brain metastases (HR 2.65, 95% CI 1.06-6.60, P = 0.037) and prior chemotherapy (HR 3.17, 95% CI 1.35-7.45, P = 0.008) had a higher risk of progression. Sixteen patients received subsequent lorlatinib, with an ORR of 28% and mPFS of 3.7 months. G2032R and L2026M resistance mutations were identified in four lorlatinib non-responders, and in vitro studies confirmed resistance to lorlatinib. Fusion partners did not affect crizotinib outcomes. Lorlatinib was ineffective against on-target resistance. Real-world data showed lower TKI efficacy than clinical trials, highlighting the role of clinical and molecular factors in treatment response.

Undifferentiated pleomorphic sarcoma (UPS) is a rare cancer with limited systemic treatment options and poor outcomes. To seek novel therapeutic interventions, we undertook mutational analysis of 20 UPS patient tumours, four established UPS cell lines and three patient-derived xenograft (PDX) models. Frequently mutated genes were uncommon; in contrast, copy number (CN) events were common with CN gain frequently observed at genes including JUN, EGFR and CDK6 and loss at WNT8B, RB1 and PTEN. Analysis of overlapping genomic changes between patient tumours and PDX models or cell lines revealed druggable events. A selected panel of drugs targeting these was analysed in in vitro UPS models demonstrating that the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib is synergistic in combination with the fibroblast growth factor receptor (FGFR) inhibitor infigratinib. This was further confirmed to be efficacious in an ex vivo tumour slice model. Taken together, our results demonstrate the rationale for utilising genomic data to identify drug classes targeting druggable events in low-prevalence cancers and indicate that trametinib alone or in combination with infigratinib should be further explored for clinical UPS management.

Melanoma, the deadliest form of skin cancer, poses a significant challenge due to its genetic heterogeneity and high metastatic potential. While cytotoxic T cell (CTL)-based immunotherapies have made remarkable progress in recent years, the therapeutic potential of natural killer-(NK) cells is increasingly recognized. However, resistance mechanisms to both CTL- and NK-cell-mediated immunotherapies hinder effective treatment. To evaluate the exclusive role of NK-cells in anti-melanoma immunity, we performed 2D and 3D co-culture-based cytotoxicity assays under varying conditions. Our findings revealed a protective phenotype in melanoma cells following prolonged exposure to primary NK-cells. By combining experimental data with bioinformatic analyses, we identified key genes and pathways involved in melanoma cell adaptation to NK-cell-mediated killing (NKmK). We found that cytokines such as IFNγ play a major role in suppressing NKmK with MHC II surface expression being a critical factor. Targeting the master regulator CIITA, which governs MHC II expression and is affected by IFNγ, significantly reduced melanoma cell resistance to NKmK. This study provides potential strategies to overcome resistance to NK-cell-based immunotherapies and offers novel insights into melanoma immune escape mechanisms.

While radioactive iodine therapy (RAIT) has been an effective treatment for thyroid cancer, its link to clonal hematopoiesis (CH) has been yet underexplored. In this study, error-corrected sequencing (median depth: 1926×) of 93 CH-related genes was performed from the blood samples of 358 thyroid cancer patients, including 110 controls (no RAIT) and 248 RAIT recipients. RAIT recipients were stratified into low- and high-dose groups using a 7.4 GBq cutoff. Multivariable logistic regression revealed that the high-dose group had a higher CH prevalence with variant allele frequency (VAF) higher than 2% compared to controls, especially in patients aged ≥50 (OR = 2.44, CI = 1.04-6.00, P = 0.04). Thirteen genes had mutations with VAF >2%, with DNMT3A, TET2, and PPM1D being the most common. Notably, only the PPM1D mutations were significantly linked to RAIT, occurring more frequently in the high-dose group (13%) compared to the low-dose group (5%) or controls (2%) at a VAF cutoff of 0.5%. In silico analyses indicated that truncating PPM1D mutations confer a selective advantage under high-dose RAIT and with older age. Although the prognostic implications of PPM1D-mutated CH remain to be further elucidated, these findings offer valuable insights for optimizing RAIT dosing in thyroid cancer patients.

Triple-negative breast cancer (TNBC) remains the breast cancer subtype with the poorest prognosis. While PARP inhibitors (PARPi) effectively target BRCA1/2-mutant TNBCs via synthetic lethality, most TNBCs are BRCA1/2 wild-type. Synergistic drug combinations may expand PARPi efficacy to BRCA-proficient TNBC. To identify new PARPi combinations, we screened a library of 166 FDA-approved oncology drugs for synergy with Olaparib in TNBC cells. We found that Exemestane, an aromatase inhibitor, synergized with Olaparib, significantly decreasing IC₅₀ values and clonogenicity while increasing DNA damage and apoptosis. The mechanistic basis for this synergy was rationalized by the previously unreported ability of Exemestane to induce replication stress via reactive oxygen species (ROS) generation and oxidative stress. This combination had low cytotoxicity toward normal breast epithelial cells, and Exemestane has no reported severe toxicity as a monotherapy. The combination of Olaparib and Exemestane was able to achieve enhanced tumor growth inhibition in a murine xenograft model, greater than either drug employed as a single agent, and GO and KEGG enrichment analysis indicated alterations in pathways associated with cell death in response to Exemestane and Olaparib treatment.

Ovarian cancer (OC) has the highest mortality rate of all gynaecological malignancies, partly attributable to its propensity for chemotherapy resistance. The most common subtype of OC is serous, of which high-grade serous ovarian cancer (HGSOC) is the most lethal subtype. Protein tyrosine phosphatase 4A3 (PTP4A3) overexpression is implicated in tumour cell invasion and metastasis by upregulating the PI3K/Akt/mTORC1 axis. Previously, we reported that PTP4A3 increased the survival of non-serous OC cells by activating the autophagy pathway. Here, we investigated the impact of PTP4A3 on cell proliferation, autophagy and chemoresistance in HGSOC cells and whether targeting PTP4A3 in HGSOC cells that overexpress this phosphatase would sensitise them to existing chemotherapeutic drugs. Gene silencing of PTP4A3 resulted in the upregulation of compensatory mechanisms that overcame the loss of PTP4A3 expression, but this was mitigated by pan-PTP4A inhibition with JMS-053 in HGSOC cells. Moreover, shRNA-mediated silencing of PTP4A3 sensitised HGSOC cells to clinically relevant chemotherapeutic drugs. Overall, we show that compensatory mechanisms from PTP4A1 and PTP4A2 can arise when specifically targeting PTP4A3 in HGSOC and that pan-PTP4A inhibition can overcome those effects.