Translational Oncology最新文献

MYC amplification is disproportionally elevated in triple-negative breast cancer (TNBC) compared to other subtypes of breast cancer. Indeed, MYC has long been considered an undruggable oncogene using conventional drug design strategies or small molecules. We hypothesized that targeting MYC using asymmetric siRNA (asiRNA) alone or in combination with chemotherapeutic agents or indirectly via BRD4 and RRM2, may curb its oncogenic behavior. We developed paclitaxel-, doxorubicin-, and cisplatin-resistant MDA-MB-231 cells to study MYC's role in upregulating DNA repair genes during drug resistance development. Our results showed that the knockdown of either MYC or RRM2 downregulated both RAD51 and PARP1 but increased γH2AX. The cytotoxic effect of RRM2 knockdown was significantly (p < 0.05) higher than that of direct MYC knockdown. The knockdown of BRD4 was more effective than the direct knockdown of MYC in downregulating MYC protein. The combined use of asiRNA-VP (Vinylphosphonate) with dacomitinib or talazoparib was synthetic lethal in TNBC cell lines. Compared to chemotherapy-sensitive cells, resistant cells showed overexpression of MYC, RRM2, RAD51, and PARP1 proteins upon chemotherapy treatment, but downregulated in cells treated with asiRNA-VP combination. We confirmed that MYC knockdown upregulated cFLIP, BCL2, STAT1, pSTAT1, STAT2, and cleaved saspase-3 in both TNBC and non-small cell lung cancer (NSCLC) cell lines. Finally, we recommend a combination treatment approach that synergizes with MYC inhibition rather than monotherapy or indirect targeting via upstream regulators such as the BRD4 and RRM2 genes or selective modulation at the protein level to suppress anti-apoptotic genes (cFLIP and BCL2) at the same time.

Our experimental study showed that METTL3 was highly expressed in NSCLC cells and promoted the growth of tumor cells. METTL3 takes N6-methyladenosine (m6A) as the main means of mRNA modification to control the expression and function of RIG-I-MAVS signalling pathway. RIG-I-MAVS constitute the first line frontier in the innate immune defense of human cells. Activation of RIG-I-MAVS signaling can inhibit tumor cell growth and activate the immune microenvironment. Our experimental data reveal that lung cancer cells utilize METTL3-mediated methylation modifications to inhibit the activation of RIG-I-MAVS signaling pathway and immune responses. Our work provides new ideas for biotherapy and immunotherapy.

The treatment of colorectal cancer (CRC) poses significant challenges in terms of drug resistance and poor prognosis, necessitating the exploration of effective therapeutic strategies. In this study, high-throughput drug screening was utilized to identify Chinese herbal medicines with notable therapeutic effects on CRC. Among the compounds identified, 4'-demethylpodophyllotoxin (DOP), a derivative of podophyllotoxin, emerged as a potent anti-cancer compound. DOP exhibited time- and dose-dependent growth inhibition on CRC cell lines and tumor organoids derived from patients. RNA-seq revealed that DOP activated the PI3K-AKT pathway, leading to tumor cell apoptosis and cell cycle arrest at the G2/M phase. Additionally, DOP induced DNA damage in CRC cells. To further validate its therapeutic efficacy in CRC, the DLD1-derived xenograft model demonstrated that DOP effectively suppressed CRC growth in vivo. In conclusion, these findings highlight the significant therapeutic potential of DOP as an anti-tumor drug for treating CRC, thereby opening new avenues for investigating Podophyllotoxin derivatives in this specific field.

Background: Circulating tumor DNA (ctDNA) revolutionized the molecular diagnostics of lung cancer by enabling non-invasive, sensitive identification of actionable mutations. However, ctDNA analysis may be challenging due to tumor shedding variability, leading to false negative results. This study aims to understand the determinants for ctDNA shedding based on clinical characteristics of lung cancer patients, for a better interpretation of false negative results to be considered when ordering ctDNA analysis for clinical practice.

Methods: Blood samples were collected from patients with stage IV EGFR-mutated (mEGFR) NSCLC before treatment and monitored until disease progression. EGFR was assessed on tissue by standard procedures, while EGFR status on ctDNA was tested using dPCR at baseline and at the first reassessment. NGS was used to evaluate patients mutational status at the progression of the disease.

Results: A total of 40 mEGFR tissue samples were collected. Plasma samples were analyzed for mEGFR before starting the first line, 65 % of patients had detectable mEGFR in ctDNA ("shedders"). Higher ECOG PS (p = 0.04), bilateral localization of primary tumor (p = 0.04), and the presence of intrathoracic/extrathoracic disease (p = 0.05), were associated to mEGFR shedding. Shedders had shorter PFS compared to non-shedders (p = 0.03). Patients with detectable mEGFR in ctDNA at the first radiological assessment exhibited worse PFS compared to patients with ctDNA clearance (p = 0.05).

Conclusion: Our preliminary data demonstrate that specific clinical characteristics predict mEGFR shedding in ctDNA of NSCLC, suggesting a potential clinical applicability for understanding potential false negative results and appropriate reporting in clinical practice.

It has been well established that tumor-infiltrating lymphocytes (TILs) play a critical role in the pathogenesis and progression of clear cell renal cell carcinoma (ccRCC). However, the mechanism on the interactions between TILs and tumor cells in the tumor-immune microenvironment remains unclear. In the present study, the expression of Response Gene to Complement 32 (RGC-32) was evaluated using immunohistochemistry. We analyzed the associations of RGC-32 expression with patient characteristics and survival. We also assessed TILs and their subsets (CD3⁺, CD4⁺, CD8⁺ and PD-1⁺) in the tumor nest. The level of RGC-32 expression was positively correlated with ISUP grade and Ki67 expression and was an independent poor prognosis factor of patients with ccRCC. RGC-32 expression was negatively correlated with the infiltration of TIL and CD3⁺T cells, but positively correlated with infiltration of PD-1⁺cells. In vitro studies showed that RGC-32 expression in renal cancer cells was downregulated by activated immune cells. Further investigation revealed that RGC-32 expression in renal cancer cells was inhibited by TNF-α and IL-1β secreted by activated immune cells. Collectively, these data indicate that RGC-32 could be a novel prognostic and druggable target related to the tumor-immune microenvironment in renal cancer.

Background: Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with poorly understood underlying molecular mechanisms. Ferroptosis, a form of programmed cell death, is not fully elucidated in NPC.

Method: We conducted quantitative proteomics to detect dysregulated proteins in NPC tissues. The levels of endoplasmic reticulum membrane protein complex 2 (EMC2) in NPC tissue microarrays were evaluated by immunohistochemistry, and the prognostic value of EMC2 was analyzed in NPC patients. The role of EMC2 in ferroptosis and carcinogenesis was determined through in vitro and in vivo experiments. Quantitative proteomics, protease inhibition, ubiquitin detection, and rescue experiments were performed to explore the mechanism of EMC2-regulated ferroptosis.

Results: Significantly upregulated EMC2 was detected in NPC, and it was closely related to the characteristics of tumor progression. Elevated EMC2 was obviously correlated with poor survival in patients with NPC. EMC2 knockdown promoted ferroptosis, inhibiting cell viability, migration, and invasion, and enhancing the efficacy of cisplatin in NPC cells. Conversely, EMC2 overexpression contributed to ferroptosis repression, malignant progression, and reduced the efficacy of cisplatin. In addition, EMC2 knockdown suppressed xenograft tumor growth and enhanced ferroptosis in nude mice. Mechanistically, we identified transferrin receptor (TFRC) as a critical downstream protein. EMC2 interacted with TFRC and promoted its ubiquitin-proteasomal degradation. EMC2 regulated ferroptosis by mediating the level of TFRC.

Conclusions: EMC2 suppresses ferroptosis and promotes tumor progression, and the EMC2-TFRC axis is a novel ferroptosis regulatory pathway. EMC2 is a potentially biomarker and therapeutic target for NPC.

Objective: To evaluate the efficacy and safety of the continuing immunotherapy as subsequent therapy in extensive-stage small cell lung cancer (ES-SCLC) patients who have progressed after initial immunotherapy.

Methods: A retrospective analysis was conducted on patients with ES-SCLC who experienced disease progression after receiving programmed cell death ligand 1 (PD-L1) inhibitors combined with standard chemotherapy as first-line treatment at three sites in China. Patients were divided into two groups according to whether to continue second-line immunotherapy.

Results: In a cohort of 150 ES-SCLC patients evaluated post-progression following first-line PD-L1 inhibitors, second-line treatment regimens varied: 86 patients received immunotherapy beyond progression (IBP) and 64 did not proceed to second-line immunotherapy (non-IBP). IBP significantly increased both disease control rates (DCR, 68.6% vs. 32.8%, p<0.001) and overall response rate (ORR, 33.7% vs. 15.6%, p=0.012) and extended median progression-free survival (PFS, 4.1 vs. 2.4 months, HR=0.46, p<0.001) when compared with non-IBP group. The median overall survival (OS) in the IBP group was also longer than that in the non-IBP group (11.2 months vs. 9.0 months, HR=0.68, 95%CI 0.47-0.98, p=0.042). Subgroup analyses revealed a significant survival advantage with IBP treatment in patients presenting with baseline liver metastases, less than three metastatic organs, and those who were nonsmokers.

Conclusions: In patients with ES-SCLC who received first-line PD-L1 inhibitors, continuing IBP extended second-line survival without increasing adverse events (AEs). A more pronounced OS benefit with IBP was noted within specific patient subgroups.