Anti-Cancer Drugs最新文献

Melanoma is one of the most lethal forms of skin cancer, driving continuous research efforts to discover effective therapeutic strategies. Phytochemicals are promising for antimelanoma drug development because of their multitarget bioactivities. 9-Methoxycamptothecin (MCPT), a plant-origin compound, has demonstrated potent anticancer activity against various human cancers; however, its inhibitory effects on melanoma and the underlying molecular mechanisms remain incompletely understood. In this research, human melanoma cell lines (A375, SKMEL28) were treated with MCPT. Cell proliferation was evaluated using MTT and clonogenic assays. Cell cycle and apoptosis were assessed by flow cytometry. The MCPT-induced DNA damage in melanoma cells was observed via immunofluorescence staining of γ-H2AX. Protein expression was analyzed by western blotting. Proliferating cell nuclear antigen associated factor 15 (PAF15) was overexpressed via lentiviral transduction to evaluate its functional role in MCPT response. The antimelanoma effect of MCPT in vitro was studied in BALB/c nude mice bearing subcutaneous tumors from A375 cells. The results showed that MCPT suppressed melanoma cell proliferation via inducing the G2/M phase cell cycle arrest. Meanwhile, MCPT induces caspase-dependent apoptosis and DNA damage in melanoma cells. In vivo , MCPT effectively inhibited the growth of melanoma xenografts. Crucially, these MCPT-mediated effects were partly rescued by exogenous PAF15 overexpression. In conclusion, MCPT exerts antimelanoma effects by inhibiting proliferation, inducing cell cycle arrest, DNA damage, and apoptosis. Importantly, these effects are critically mediated through the downregulation of PAF15.

Regorafenib, a multikinase inhibitor, is widely used to treat hepatocellular carcinoma. However, chemoresistance poses a significant challenge to its long-term efficacy. This study conducted a genome-wide CRISPR/Cas9 knockout screen in liver cancer cell lines to identify key regulators of regorafenib resistance and elucidate the underlying molecular mechanisms. The screen identified ARHGAP35 as a critical negative regulator of regorafenib resistance. ARHGAP35 depletion conferred resistance in HepG2 and Huh7 cells, while regorafenib-resistant variants (HepG2-R and Huh7-R) exhibited decreased ARHGAP35 expression. Reintroducing ARHGAP35 restored drug sensitivity. Further analysis revealed that reduced ARHGAP35 expression facilitated epithelial-mesenchymal transition (EMT) by activating the RhoA signaling pathway. Notably, RhoA inhibition reversed EMT and restored regorafenib sensitivity. These findings highlight ARHGAP35 as a key modulator of regorafenib resistance through RhoA suppression, offering potential therapeutic targets to combat chemoresistance in liver cancer.

KRAS -mutant non-small cell lung cancer (NSCLC) remains a major therapeutic challenge due to the paucity of effective targeted agents. Although covalent KRAS^G12C inhibitorsi such as sotorasib and adagrasib have demonstrated clinical activity, pooled analyses indicate only modest response rates and short progression-free survival, with no effective options for non-G12C subtypes. This highlights the need for novel therapeutic strategies with broader efficacy and improved durability. We evaluated the antiproliferative effects of SP09, a novel benzoin-Schiff base derivative, in KRAS -mutant (A549, H460) and EGFR -mutant (PC9) NSCLC cells, as well as normal lung cells. Cell viability, colony formation, and cell cycle distribution were assessed, and the involvement of the liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) signaling axis was examined by western blot. SP09 selectively inhibited the proliferation of KRAS -mutant NSCLC cells (IC 50 ≈ 29 µM) with minimal toxicity to normal lung cells. Treatment induced G2/M arrest via downregulation of cyclin B1 and upregulation of p21. Mechanistically, SP09 activated the LKB1/AMPK pathway and suppressed mTOR signaling, leading to inhibition of downstream effectors, including P70S6K, S6, and sterol regulatory element-binding protein 1 (SREBP1). SP09 exerts potent and selective antiproliferative effects in KRAS -mutant NSCLC through dual regulation of cell cycle and metabolic signaling pathways. Given the restricted efficacy and rapid resistance associated with current KRAS -targeted therapies, our data highlight SP09 as a promising candidate for further preclinical development with potential translational value in KRAS -driven NSCLC.

Chemotherapy resistance remains a major challenge in the treatment of uveal melanoma, necessitating the identification of novel therapeutic strategies. In this study, we established chemoresistant uveal melanoma cell lines by exposing parental cells to dacarbazine, cisplatin, or gemcitabine and performed high-throughput drug screening incorporating normal human epidermal melanocytes (NHEMs) as a normal control to assess both efficacy and selectivity. Our screening identified temsirolimus and selumetinib as top candidates, with temsirolimus exhibiting strong tumor-selective cytotoxicity. Further in-vitro studies confirmed that temsirolimus induced apoptosis and suppressed clonogenic potential in chemoresistant uveal melanoma cells while having minimal effects on NHEM. Combination studies demonstrated synergy between temsirolimus and cisplatin or gemcitabine, reinforcing its role as an effective chemosensitizer. In a chemoresistant uveal melanoma xenograft model, temsirolimus significantly inhibited tumor growth without inducing systemic toxicity, as evidenced by stable biochemical markers of organ function. Mechanistically, temsirolimus downregulated mammalian target of rapamycin (mTOR) signaling, as indicated by reduced p-mTOR, p-S6, and p-4EBP1 expression in tumor tissues. These findings demonstrate that temsirolimus selectively targets chemoresistant uveal melanoma cells, enhances chemotherapy efficacy, and suppresses tumor growth via mTOR inhibition, supporting its potential clinical application as a novel therapeutic strategy for chemoresistant uveal melanoma.

Tafasitamab, an anti-CD19 mAb, has demonstrated promising efficacy in relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in Western populations, but its use in Chinese patients has not been reported. This case series reports the use of tafasitamab in four Chinese patients with R/R DLBCL. Four patients with R/R DLBCL were treated at the Department of Hematology, Hainan Hospital of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. All patients had previously received rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone therapy. After treatment with tafasitamab and lenalidomide, two patients with primary refractory disease, one achieved a partial response and another had stable disease. One patient who relapsed after autologous stem-cell transplantation received tafasitamab plus lenalidomide and a Bruton tyrosine kinase (BTK) inhibitor and showed remarkable tumor reduction in all sites except for the lymph nodes in the left inguinal region. One patient who relapsed after second-line therapy achieved complete remission with tafasitamab monotherapy. Tafasitamab-based treatment was well-tolerated, with the most common adverse event being neutropenia. Our real-world experience first suggests that tafasitamab-based flexible treatment may be a potential treatment option for Chinese patients with R/R DLBCL, supporting the need for further investigation into its efficacy and safety in Chinese patients, with a particular focus on exploring directions such as combinations with BTK inhibitors.

As epidermal growth factor receptor ( EGFR ) exon 20 insertion mutations generally result in poor sensitivity to EGFR -tyrosine kinase inhibitors (TKIs), the administration of EGFR -TKIs is not recommended in non-small-cell lung cancer (NSCLC). Nonetheless, EGFR exon 20 A763_Y763insFQEA, a genotype of EGFR exon 20 insertion mutations, has some sensitivity to EGFR -TKIs. However, the therapeutic effects of EGFR -TKIs alone for EGFR exon 20 A763_Y763insFQEA are insufficient compared to those for common EGFR mutations. Therefore, more effective treatment options are required for this mutation. Herein, we present a case in which treatment with erlotinib plus ramucirumab led to a complete response and progression-free survival of 13 months in a 79-year-old man with advanced NSCLC harboring EGFR exon 20 A763_Y763insFQEA. This case suggests that this regimen should be considered as an effective treatment option for such patients.

Chemotherapy improves outcomes in patients with high-risk early or locally advanced breast cancer, but older adults often experience higher toxicity that leads to treatment delays, dose reductions, and reduced relative dose intensity (RDI). This study examined predictors of low RDI and its impact on overall survival (OS) in women aged over 65 years treated with neoadjuvant or adjuvant chemotherapy at San Juan de Dios Hospital (Costa Rica) between November 2018 and April 2023. A total of 264 patients (mean age: 70.1 years) were included. Nearly one-third had a Charlson Comorbidity Index (CMI) greater than 6. Tumor subtypes were hormone receptor (HR)+/ human epidermal growth factor receptor (HER2)-(48.9%), HR+/HER2+ (15.9%), HR-/HER2+ (33%), and triple-negative (17.8%). Most patients (68.6%) received anthracycline-based regimens. Overall, 17.4% had an RDI below 80%. After a median follow-up of 54.6 months, 56 deaths were recorded. Low RDI was significantly associated with worse OS [hazard ratio: 1.79, 95% confidence interval (CI): 1.02-3.13; P = 0.04]. Independent predictors of low RDI were anthracycline-based therapy [odds ratio (OR): 4.76, 95% CI: 2.17-9.09], CMI greater than 6 (OR: 2.13, 95% CI: 1.02-4.54), and age more than 70 years (OR: 2.38, 95% CI: 1.14-5.01). These findings suggest that advanced age, comorbidities, and anthracycline regimens increase the risk of reduced RDI, which negatively impacts survival. Supportive measures are critical to maintain chemotherapy intensity in older women.

Salivary duct carcinoma (SDC) is a rare and highly aggressive malignancy that frequently overexpresses Human Epidermal Growth Factor Receptor 2 (HER2). Despite the increasing recognition of HER2-targeted strategies, evidence remains limited and largely derived from small trials and case series. We report the case of a middle-aged man with HER2-positive metastatic SDC who achieved near-complete pathologic and radiological response to trastuzumab and docetaxel, enabling surgical resection for locoregional control. This case highlights the role of anti-HER2 therapy as a first-line strategy in SDC and underscores the importance of individualized management plans integrating systemic treatment and locoregional measures.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy represent the standard of care for hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (mBC). While clinical trials established their efficacy, real-world evidence on safety, dose adjustments, and outcomes remains limited. We conducted a prospective observational study including patients with HR+/HER2- mBC treated with palbociclib, ribociclib, or abemaciclib across three oncology units between 2019 and 2024. Data on adverse events, dose modifications, progression-free survival (PFS), and overall survival (OS) were collected and analyzed. Adverse events were reported in 77.5% of patients. Neutropenia was the most frequent adverse event with palbociclib and ribociclib, while diarrhea and hepatic toxicity predominated with abemaciclib. Pulmonary toxicity occurred in 19.1% of abemaciclib-treated patients, often in those previously irradiated. Median PFS and OS were 26.4 and 31.1 months, respectively. The occurrence of grade 3-4 adverse events correlated with improved OS (37.1 vs. 23.0 months, P < 0.001). Dose reductions, required in more than 60% of patients, did not compromise efficacy; instead, they were associated with longer PFS and OS. Conversely, treatment discontinuation predicted worse outcomes. In real-world practice, CDK4/6i toxicities are frequent but manageable. Proactive toxicity management and timely dose adjustments are essential to sustain treatment benefit. Dose reductions may even improve outcomes, underscoring the value of individualized dosing strategies.

Scirrhous gastric cancer (SGC), including the Borrmann type IV subtype, is characterized by a desmoplastic stroma, rapid progression, and a poor prognosis with limited effective treatment options. While fibroblast growth factor receptor 2 (FGFR2) alterations are recognized therapeutic targets in some cancers, their clinical application in gastric cancer, particularly in SGC, remains underexplored. We present the case of a 47-year-old female with advanced, chemotherapy-refractory Borrmann type IV gastric cancer harboring FGFR2 rearrangement and amplification. Treatment with the selective FGFR1-3 inhibitor pemigatinib elicited a marked clinical and serological response; however, disease progression ensued after 3 months. Comprehensive genomic profiling revealed an acquired FGFR2 N549K mutation, a recognized on-target resistance mechanism. Subsequent administration of the irreversible FGFR1-4 inhibitor futibatinib was associated with a declining trend in tumor biomarkers, indicating preliminary antitumor activity against the resistant clone. This case underscores the clinical activity of FGFR inhibition in FGFR2-altered SGC and exemplifies the emergence of kinase domain mutations as a principal resistance pathway. It further suggests that irreversible FGFR inhibitors may represent a rational therapeutic strategy upon progression on prior FGFR-directed therapy, warranting further clinical investigation in this molecularly defined patient subset.