Anti-cancer Drugs[JOURNAL]
Sun
200 papers
Akt inhibitor-IV in estrogen receptor-positive breast cancer cells: cytotoxic, apoptotic, transcriptional, and in-silico comparison with tamoxifen.
Karakuş A, Erdoğan O
Anticancer Drugs · 2026 Jul · PMID 42390376 · Publisher ↗
Dysregulation of the phosphoinositide 3-kinase/protein kinase B (AKT)/mechanistic target of rapamycin pathway is a hallmark of breast cancer, making AKT a focus of therapeutic interest. AKT inhibitor-IV is a benzimidazol...
Dysregulation of the phosphoinositide 3-kinase/protein kinase B (AKT)/mechanistic target of rapamycin pathway is a hallmark of breast cancer, making AKT a focus of therapeutic interest. AKT inhibitor-IV is a benzimidazolium compound that inhibits AKT phosphorylation, but its activity and binding mechanism in breast cancer cells have not been characterized in detail. We compared AKT inhibitor-IV with tamoxifen in MCF-7 cells. Cell viability after 24-h treatment was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay (AKT inhibitor-IV: 0.1-5 μM; tamoxifen: 5-50 μM); apoptotic death was quantified by nucleosome ELISA; and AKT1, BCL-2, BAX, and CASP3 mRNA levels were measured by quantitative real-time PCR. Both compounds were docked into the ATP-binding pockets of 3-phosphoinositide-dependent protein kinase-1 (PDK1) (PDB 1H1W) and AKT1 (PDB 3MVH) using AutoDock Vina v1.2.6. AKT inhibitor-IV reduced viability with an IC50 of 1.1 μM, compared with 5.2 μM for tamoxifen, and induced 5.9-fold apoptosis enrichment versus 3.65-fold for tamoxifen. AKT inhibitor-IV downregulated AKT1 (0.32-fold) and BCL-2 (0.55-fold) and upregulated BAX (5.97-fold) and CASP3 (6.43-fold) mRNA; tamoxifen showed qualitatively similar but quantitatively weaker transcriptional changes. Docking returned affinities of -9.91 kcal/mol for PDK1 and -9.66 kcal/mol for AKT1, with AKT inhibitor-IV contacting catalytic-core residues of both kinases. AKT inhibitor-IV was more potent than tamoxifen in this in-vitro setting and warrants further preclinical evaluation. Because MCF-7 cells carry the CASP3 exon 3 deletion and lack functional caspase-3 protein, the observed CASP3 mRNA upregulation reflects transcriptional reprogramming rather than restored executioner activity. The modest docking difference requires biochemical confirmation before any PDK1-versus-AKT1 selectivity claim can be established.
Prolonged multimodal disease control with trifluridine/tipiracil plus bevacizumab in KRAS-mutant metastatic rectal cancer: a case report.
Alkan O, Başgöze A, Nazli İ
Anticancer Drugs · 2026 Jun · PMID 42307975 · Publisher ↗
Refractory metastatic colorectal cancer (mCRC) management is further complicated when fluoropyrimidine-based therapy is contraindicated, leaving few systemic options. We present a 57-year-old man with KRAS G13D-mutant, l...
Refractory metastatic colorectal cancer (mCRC) management is further complicated when fluoropyrimidine-based therapy is contraindicated, leaving few systemic options. We present a 57-year-old man with KRAS G13D-mutant, liver-dominant metastatic rectal adenocarcinoma and recurrent fluoropyrimidine-associated coronary vasospasm precluding 5-fluorouracil and capecitabine. After multimodal first-line therapy and regorafenib, trifluridine/tipiracil (TAS-102) plus bevacizumab was initiated and integrated with liver-directed treatments for oligoprogressive disease. This combined strategy achieved approximately 16.6 months of disease control, substantially exceeding the median progression-free survival reported in the SUNLIGHT trial, with manageable hematological toxicity and preserved performance status. This case highlights the value of TAS-102 plus bevacizumab combined with focal liver-directed therapy as a feasible long-term strategy for selected patients with oligoprogressive mCRC when fluoropyrimidines cannot be used.
Growth differentiation factor-11 inhibits the progression of acute myeloid leukemia and increases chemosensitivity by inhibiting cathepsin S.
Luo J, Xu Y, Zhang L … +1 more , Ding L
Anticancer Drugs · 2026 Jun · PMID 42307925 · Publisher ↗
Growth differentiation factor-11 (GDF11) is an important member of the transforming growth factor-β superfamily and plays an important role in tumor progression. However, its role and prognostic value in acute myeloid le...
Growth differentiation factor-11 (GDF11) is an important member of the transforming growth factor-β superfamily and plays an important role in tumor progression. However, its role and prognostic value in acute myeloid leukemia (AML) have not been reported. We overexpressed GDF11 to investigate the effect of GDF11 on the behavior of AML cells. The effect of GDF11 on chemotherapy sensitivity was investigated in HL60 cells treated with 10 μM daunorubicin (DNR). Cell viability was detected using the cell counting kit-8 assay. Western blot was performed to analyze the expression levels of target proteins. GDF11 was associated with poor overall survival of AML patients. The proliferation of HL60 cells was inhibited by the transfection of pcDNA3.1-GDF11. GDF11 overexpression upregulated the expression of caspase3-p17 and Bax, while downregulating the Bcl-2 level. Importantly, the decreased cell proliferation and induced apoptosis by DNR were enhanced by GDF11 overexpression. Cathepsin S (CTSS) expression was inhibited by GDF11 in HL60 cells. The overexpression of CTSS attenuated the enhancement of GDF11 on chemotherapy sensitivity. In addition, CTSS activated the extracellular signal-regulated kinase 1 and 2 signaling pathway and inhibited endoplasmic reticulum stress in AML cells. In conclusion, GDF11 inhibited the growth and increased chemosensitivity through inhibiting CTSS expression in AML cells, providing potential therapeutic targets for AML treatment.
Inavolisib and lenvatinib for PIK3CA-mutated refractory splenic angiosarcoma: a case report.
Zhao X, Wang C, Ge Y … +5 more , Song D, Guan A, Hu J, Nie Y, Guan M
Anticancer Drugs · 2026 May · PMID 42307901 · Publisher ↗
Primary splenic angiosarcoma (PSA) is a rare vascular malignancy with a poor prognosis and limited therapeutic options. A 62-year-old man with metastatic PSA underwent splenectomy followed by first-line paclitaxel, achie...
Primary splenic angiosarcoma (PSA) is a rare vascular malignancy with a poor prognosis and limited therapeutic options. A 62-year-old man with metastatic PSA underwent splenectomy followed by first-line paclitaxel, achieving stable disease for 7 months. Disease progression manifested as hepatic and bone marrow metastases with tumor-induced hepatic failure and refractory thrombocytopenia. Sequential treatment with liposomal doxorubicin, eribulin, toripalimab, and lenvatinib failed to control the disease failed to control the disease. Genomic profiling identified a PIK3CA p.P471L missense mutation. A combination regimen of inavolisib (a selective PI3Kα inhibitor) and lenvatinib was initiated. Bilirubin levels normalized, and platelet counts recovered within 2 weeks; follow-up MRI confirmed radiological stabilization. At 16 months postdiagnosis, the patient remains alive on this regimen, though long-term durability of response has yet to be determined. To our knowledge, this is the first reported use of inavolisib in angiosarcoma. The rapid biochemical and radiological response observed in this PIK3CA-mutated PSA supports early genomic profiling to identify actionable alterations and warrants prospective evaluation of combined phosphoinositide 3-kinase and vascular endothelial growth factor pathway inhibition in refractory angiosarcoma.
Drug repurposing of liver cancer based on multimodal neural network and virtual screening.
Huang X, Jia X, Zhou Y … +2 more , Chang Z, Zhang X
Anticancer Drugs · 2026 May · PMID 42234871 · Publisher ↗
Liver cancer is a malignant tumor with high incidence and mortality rates globally. Existing therapeutic methods have certain limitations in terms of efficacy, safety, and applicability, creating an urgent need for the d...
Liver cancer is a malignant tumor with high incidence and mortality rates globally. Existing therapeutic methods have certain limitations in terms of efficacy, safety, and applicability, creating an urgent need for the development of new treatment strategies. Drug repurposing, which explores new indications for already approved drugs, offers significant advantages in reducing research and development costs and shortening development timelines. This study utilized a multimodal neural network model to integrate molecular fingerprints and molecular graphs to construct a drug-target interaction prediction system for liver cancer targets. A large-scale virtual screening of The US Food and Drug Administration-approved drugs was conducted, followed by molecular docking and molecular dynamics simulations to analyze binding stability. The screening identified 17 potential antiliver cancer drugs. Further verification of their in-vitro activity was performed through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and wound healing assays in MHCC97-H, HepG2, and Huh7 cell lines, revealing that Manidipine and Vildagliptin exhibited significant cytotoxicity and migration inhibition. These results demonstrate the feasibility of the proposed screening workflow and provide a set of candidate molecules for further mechanistic investigation in liver cancer drug repurposing.
Discovery of an orally active and liver-targeted dual prodrug of 5-fluoro-2'-deoxyuridine-5'-monophosphate for the treatment of hepatocellular carcinoma.
Yang M, Dai XL, He CW … +10 more , Fang HX, Yan J, Bai RX, Hao J, Sun ZM, Liu XH, Cui SX, Wan WJ, Hao JJ, Qu XJ
Anticancer Drugs · 2026 Jun · PMID 42234855 · Publisher ↗
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally. Hepatic arterial infusion chemotherapy with 5-fluorouracil (5-FU) have been considered; however, it has limited survival benefits becau...
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally. Hepatic arterial infusion chemotherapy with 5-fluorouracil (5-FU) have been considered; however, it has limited survival benefits because of unbearable toxicity. Hence, a series of 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) prodrugs was designed and synthesized using ProTide technology. By favorable membrane permeability and bypassing enzymatic activation pathway of 5-FU to FdUMP, DL series of ProTide prodrugs circumvented mechanisms of 5-FU resistance and avoided the generation of associated toxic catabolites, resulting in enhanced anti-HCC efficacy and weak toxicity. Antiproliferative activity of compounds was evaluated in both human HCC cell lines and normal hepatocytes. Further anti-HCC activity was assessed in nude mice xenografted human HepG2, HUH7, or histidine triad nucleotide-binding protein 1 (HINT1) knockdown HUH7 cells orthotopically or subcutaneously. Mechanistic studies involving HINT1-silenced cells and co-administration with HINT1 upregulation by taraxasterol were conducted to validate the mode of action. Compound DL-2 effectively inhibited HCC cell growth but exhibited minimal cytotoxicity toward normal hepatocyte cell lines. DL-2 exhibited anticancer activity through bioactivation into FdUMP by hepatic HINT1. Comparatively, DL-2 weakly inhibited the orthotopic xenograft derived from HINT1-silenced human HUH7 cells. Systemic use of DL-2 did not produce significant toxicity in mice. In conclusion, we discovered an orally active and liver-targeted dual prodrug of FdUMP for the treatment of HCC. DL-2 is a promising drug used as a substitute for hepatic arterial infusion chemotherapy regimen.
The novel integrin-linked kinase inhibitor nilotinib suppresses cancer progression by promoting ubiquitylation of autoimmune regulator in oesophageal squamous cell carcinoma.
Ma X, Wei Y, Cao L … +4 more , Gao Y, Qu C, Muhetaer K, Zhang L
Anticancer Drugs · 2026 Apr · PMID 42069146 · Publisher ↗
Integrin-linked kinase (ILK) is a key oncogenic driver in oesophageal squamous cell carcinoma (ESCC). This study evaluated the antitumour effects of the novel ILK inhibitor Nilotinib and explored its downstream mechanism...
Integrin-linked kinase (ILK) is a key oncogenic driver in oesophageal squamous cell carcinoma (ESCC). This study evaluated the antitumour effects of the novel ILK inhibitor Nilotinib and explored its downstream mechanisms. In vitro, TE-1 and KYSE150 cells were assessed using Cell Counting Kit-8, lactate dehydrogenase release, colony formation, 5-ehynyl-2 ' -deoxyuridine incorporation, flow cytometry, Transwell assays, and Western blotting to confirm ILK targeting and determine functional changes. Electron microscopy and fluorescent probes with flow cytometry were used to analyse mitochondrial alterations. In vivo, a nude mouse subcutaneous xenograft model was established to examine tumour growth after peritumoural Nilotinib administration; hematoxylin and eosin staining assessed tissue changes, and immunohistochemistry measured Ki67 and cleaved-caspase 3 expression. ILK overexpression alleviated Nilotinib-induced cytotoxicity, restored proliferation, increased proliferating cell nuclear antigen (PCNA) and Ki67, and reduced cleaved-caspase 3 and cleaved poly(ADP-ribose) polymerase (PARP), supporting ILK as a primary target. Nilotinib dose-dependently inhibited proliferation, invasion, and metastasis while promoting apoptosis, accompanied by downregulation of PCNA, Ki67, [matrix metalloproteinase 2 (MMP2), MMP9, and COX2] and upregulation of cleaved-caspase 3 and cleaved-PARP. In xenografts, Nilotinib significantly reduced tumour size and weight, decreased Ki67, and increased cleaved-caspase 3.RNA sequencing identified autoimmune regulator (AIRE) as a markedly downregulated molecule following Nilotinib treatment. Cycloheximide chase assays indicated accelerated AIRE protein degradation, while MG132 partially rescued AIRE levels, implicating proteasome-dependent degradation. Overall, Nilotinib suppresses ESCC progression by inhibiting ILK and destabilising AIRE, suggesting its potential as a targeted therapy for ILK-positive ESCC.
Temozolomide-based therapy may remodel the tumor microenvironment and enhance immunotherapy sensitivity in advanced leiomyosarcoma.
Tan H, Li Z, Zhou J … +8 more , Shi S, Jiang L, Zuo L, Su A, Wang H, Sun Y, Xuan W, Chi Y
Anticancer Drugs · 2026 Apr · PMID 42069000 · Publisher ↗
Leiomyosarcoma (LMS) is characterized by inherent resistance to immune checkpoint blockade, with no conclusive evidence supporting the efficacy of programmed death-1 (PD-1)/programmed death-ligand 1 inhibitor, and it is...
Leiomyosarcoma (LMS) is characterized by inherent resistance to immune checkpoint blockade, with no conclusive evidence supporting the efficacy of programmed death-1 (PD-1)/programmed death-ligand 1 inhibitor, and it is generally classified as a nonimmunogenic sarcoma subtype. This study analyzed the therapeutic efficacy of temozolomide (TEM)-based regimens in patients with advanced LMS and evaluated pathological changes after TEM treatment to explore the potential role of immunotherapies and the mechanisms that could enhance immunotherapy sensitivity after TEM treatment. This retrospective review included patients with advanced LMS treated at the Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College. All patients initiated TEM-based treatments between September 2018 and December 2024. We evaluated patients with advanced LMS and available pathological data before and after TEM-based therapy and those who received subsequent immunotherapy. In total, 47 patients received anthracycline combined with TEM, and 18 patients received gemcitabine combined with TEM. Overall median progression-free survival (mPFS) was 10.0 months, whereas median overall survival (mOS) was 31.0 months. Among six patients who received subsequent PD-1-based immunotherapy after TEM-containing regimens, mPFS and mOS were 13.0 and 45.0 months, respectively. O6-methylguanine DNA methyltransferase negativity tended to be associated with improved survival. Post-TEM biopsies revealed dynamic changes in mismatch repair gene expression, tertiary lymphoid structure counts, and the combined positive score. TEM-based regimens are effective for advanced LMS. Furthermore, pathological changes observed after TEM treatment suggest potential modulation of the tumor microenvironment, supporting further investigation into the integration of immunotherapies in this setting.
Response of undifferentiated and dedifferentiated endometrial cancer to pembrolizumab: a case report.
Rose PG, Kelley J, Petty A … +2 more , Soslow R, Cleveland Clinic Foundation
Anticancer Drugs · 2026 Apr · PMID 42068992 · Publisher ↗
To report our experience with pembrolizumab in undifferentiated and dedifferentiated endometrial cancer. We performed an institutional review board-approved, retrospective study of computerized pharmacy records to identi...
To report our experience with pembrolizumab in undifferentiated and dedifferentiated endometrial cancer. We performed an institutional review board-approved, retrospective study of computerized pharmacy records to identify all patients with undifferentiated and dedifferentiated endometrial carcinomas treated with pembrolizumab. Eleven patients who received pembrolizumab were identified with the following stages: International Federation of Gynecology and Obstetrics stages IC (1), IIC (2), IIIB (2), IIIC2 (2), and IVB (4). One hundred and forty cycles of pembrolizumab were administered. Ten of the 11 patients were mismatch repair (MMR)-deficient. Eight of the patients received pembrolizumab in combination with chemotherapy. Three partial and two complete responses were seen. Both complete responses were seen when pembrolizumab was given with chemotherapy. Four patients were treated in the adjuvant setting with pembrolizumab had no measurable disease and were not evaluable for response but remain disease-free. Two treatment-emergent adverse effects were noted: colitis and hepatitis. Because of the very high rate of MMR deficiency in undifferentiated and dedifferentiated endometrial carcinomas, incorporation of immunotherapy to chemotherapy should strongly be considered in patients with this histologic type in advanced and early-stage disease.
Synergistic antitumor effect between Olaparib and Chidamide by regulation of MYBL2 in lung cancer.
Zhu L, Ji Z, Wang X … +6 more , Xin J, Ma L, Zhang R, Deng T, Ba Y, Liu R
Anticancer Drugs · 2026 Apr · PMID 42068974 · Publisher ↗
Recently, various basic research and clinical studies have revealed the further potential of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor Olaparib and histone deacetylase inhibitor Chidamide in lung ca...
Recently, various basic research and clinical studies have revealed the further potential of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor Olaparib and histone deacetylase inhibitor Chidamide in lung cancer. However, no research available was found to report whether there is a synergistic effect of Olaparib in combination with Chidamide. This research was conducted to investigate whether there is a synergistic effect between the two drugs and the underlying mechanism in lung cancer cell lines. Here, we treat lung cancer cell lines with Olaparib with or without Chidamide in vivo and in vitro. Based on that, we found that there were synergistic effects between Olaparib and Chidamide. Combined use of them cooperatively downregulated the expression of MYBL2, which was responsible for the downregulation of BRCA1, a main member of DNA damage repair. Simultaneously, Olaparib-induced inhibition of PARP expression leads to the 'synthetic lethality' of cells. On the other hand, MYBL2 may regulate the expression of cycle protein dependent kinase 1, causing G2M cell cycle arrest. Consequently, the combination of Olaparib and Chidamide synergistically induces cell apoptosis through synthetic lethality and cell cycle arrest to exert an antitumor effect.
Hyperthermia combined with intraperitoneal perfusion of drugs improves malignant ascites caused by gastrointestinal tumors by reshaping the tumor immune microenvironment.
Zhang Y, Wang B, Zhang J … +5 more , Han S, Xu Y, Wang Y, Yan J, Wang W
Anticancer Drugs · 2026 Apr · PMID 42068972 · Publisher ↗
Malignant ascites treatment remains challenging. Hyperthermia is a promising adjunct to intraperitoneal therapies, but its mechanisms are unclear. We aimed to investigate whether combining hyperthermia with endostatin an...
Malignant ascites treatment remains challenging. Hyperthermia is a promising adjunct to intraperitoneal therapies, but its mechanisms are unclear. We aimed to investigate whether combining hyperthermia with endostatin and cisplatin alleviates malignant ascites by reprogramming immune microenvironment. A total of 28 patients with malignant ascites were enrolled and divided into three groups: untreated, recombinant human endostatin plus cisplatin, and hyperthermia combined with recombinant human endostatin and cisplatin. Ascites volume was monitored by B-ultrasound. VEGF, IL-10, and IFN-γ levels in ascitic fluid were measured via ELISA. Immune cell proportions and macrophage polarization were analyzed by flow cytometry. A murine malignant ascites model was established. Mice were treated according to same therapeutic groupings. Tumor burden was assessed via in vivo fluorescence imaging, ascites volume measurement, body weight changes, and survival analysis. Cytokine levels and macrophage polarization in murine ascites were also evaluated. Hyperthermia combined with endostatin and cisplatin reduced ascites volume and modulated ascitic microenvironment in patients with malignant ascites. Triple therapy of hyperthermia, endostatin, and cisplatin functioned dually to eliminate pro-tumoral leukocytes in ascites and reprogram macrophages into M1 phenotypes. Hyperthermia synergized with endostatin and cisplatin to suppress malignant ascites progression, mitigate systemic toxicity, and extend survival in mice. Triple therapy modulated ascitic microenvironment and promoted macrophage M1 polarization in a murine malignant ascites model. Macrophage ablation abolished therapeutic efficacy of triple therapy in malignant ascites mice. The combined strategy of hyperthermia, endostatin, and cisplatin suppresses malignant ascites in gastrointestinal cancer through inducing M1 macrophage polarization.
Remarkable efficacy of ivonescimab-based second-line therapy in advanced lung adenocarcinoma resistant to chemoimmunotherapy: a case report.
Wang X, Yang K, Yin P
Anticancer Drugs · 2026 Apr · PMID 42068723 · Publisher ↗
PD-1/PD-L1 inhibitors combined with chemotherapy are the current standard first-line treatment for advanced lung adenocarcinoma (LUAD). However, chemotherapy typically becomes the main therapeutic approach for subsequent...
PD-1/PD-L1 inhibitors combined with chemotherapy are the current standard first-line treatment for advanced lung adenocarcinoma (LUAD). However, chemotherapy typically becomes the main therapeutic approach for subsequent treatment once the development of resistance to this initial chemoimmunotherapy, and there are limited effective treatment options available. This case report describes a 41-year-old male patient with stage IVA LUAD (PD-L1 tumor proportion score: 5%, next-generation sequencing: no mutation) who achieved a partial response (PR) with first-line camrelizumab plus pemetrexed and carboplatin, but later experienced disease progression. Upon switching to second-line therapy with ivonescimab (an anti-PD-1/vascular endothelial growth factor-A bispecific antibody) combined with docetaxel, the patient achieved a significant clinical and radiographic response, again evaluated as PR, which was sustained over 12 treatment cycles. Up to now, the progression-free survival (PFS) is more than 12 months, which is significantly longer than the 9-month PFS achieved by the first-line treatment. The regimen was well-tolerated, with only grade 1 adverse events. This case highlights the potential of ivonescimab-based therapy as an effective and manageable second-line option for patients with advanced LUAD who have progressed on prior immune checkpoint inhibitor therapy, even with low PD-L1 expression.
Prochlorperazine inhibits the proliferation of hepatocellular carcinoma cells by promoting phosphorylation of β-catenin.
Liang Y, Wang X, Tian R … +6 more , Wang X, Zhang X, Wan J, Wan L, Zhang X, Ding Y
Anticancer Drugs · 2026 Apr · PMID 42068590 · Publisher ↗
Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer and ranks as the third leading cause of cancer-related fatalities worldwide. Recently, prochlorperazine (PCZ), a synthetic antipsychotic m...
Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer and ranks as the third leading cause of cancer-related fatalities worldwide. Recently, prochlorperazine (PCZ), a synthetic antipsychotic medication, has gained attention for its potential anticancer properties. However, the specific mechanisms underlying its anticancer effects remain unclear. In this study, we have identified that PCZ effectively inhibits the proliferation of HCC cells and diminishes the number and size of HCC foci in the mouse model. Subsequent studies have revealed that PCZ can directly bind to β-catenin and enhance the phosphorylation level of β-catenin. This, in turn, inhibits the Wnt signaling pathway, thereby exerting its anticancer effects. This novel finding sheds light on the potential molecular mechanisms of PCZ as a therapeutic strategy for HCC. In summary, our study provides fresh insights into the utility of PCZ as a therapeutic option for HCC and elucidates its molecular mechanisms.
Successful treatment of hairy cell leukemia with TP53 abnormality using cladribine combined with low-dose rituximab: a case report and literature review.
Chen Z, Chen L
Anticancer Drugs · 2026 Apr · PMID 42026747 · Publisher ↗
Hairy cell leukemia (HCL) is a rare mature B-cell malignancy characterized by the BRAF V600E mutation. TP53 abnormalities in HCL are associated with poor response to standard therapies and a higher risk of relapse. We re...
Hairy cell leukemia (HCL) is a rare mature B-cell malignancy characterized by the BRAF V600E mutation. TP53 abnormalities in HCL are associated with poor response to standard therapies and a higher risk of relapse. We report an elderly male patient diagnosed with classical HCL (BRAF V600E-positive) who also presented with a TP53 deletion detected by fluorescence in situ hybridization (FISH) and bone marrow fibrosis. The patient was treated with one cycle of cladribine combined with low-dose rituximab (100 mg). The treatment was well tolerated. At the 7-month follow up, the patient achieved complete molecular remission, characterized by normalized blood counts, recovery of bone marrow morphology, disappearance of the TP53 deletion by FISH, negative minimal residual disease by flow cytometry, and reversal of bone marrow fibrosis from MF-2 to MF-0. This case suggests that the combination of cladribine and low-dose rituximab may be an effective therapeutic strategy for classical HCL with TP53 abnormality, enabling deep molecular response and reversal of associated bone marrow fibrosis. Further prospective studies are warranted to validate these findings.
SENP3-mediated deSUMOylation stabilizes programmed death-ligand 1 to promote immune evasion in hepatocellular carcinoma.
Zhang B, Zheng J, Zhao Y … +2 more , Yu Z, Zheng S
Anticancer Drugs · 2026 Feb · PMID 42019938 · Publisher ↗
Despite the clinical benefits of immune checkpoint blockade in hepatocellular carcinoma (HCC), therapeutic efficacy remains limited due to persistent immune evasion. SENP3, a SUMO2/3-specific protease sensitive to redox...
Despite the clinical benefits of immune checkpoint blockade in hepatocellular carcinoma (HCC), therapeutic efficacy remains limited due to persistent immune evasion. SENP3, a SUMO2/3-specific protease sensitive to redox regulation, has emerged as a critical regulator of protein homeostasis and immune modulation. This study investigates how SENP3 regulates programmed death-ligand 1 (PD-L1) stability through SUMOylation to facilitate immune escape in HCC. We performed comprehensive molecular and functional analyses in HCC cell lines using SENP3 manipulation strategies. PD-L1 expression and SUMOylation status were evaluated by Western blotting and Ni-NTA pulldown assays. Protein interactions were examined through coimmunoprecipitation. Functional immune assays included T cell cytotoxicity measurements using coculture systems, colony formation assays to quantify tumor cell survival, cytokine profiling by ELISA, and granzyme B (GzmB) expression analysis in CD8⁺ T cells via flow cytometry. Clinical samples and experimental models demonstrated significant SENP3 overexpression in HCC. SENP3 knockdown reduced PD-L1 abundance while enhancing T cell-mediated tumor killing, pro-inflammatory cytokine secretion, and cytotoxic GzmB expression in CD8⁺ T cells. Mechanistic studies revealed that SENP3 directly interacts with PD-L1 and catalyzes its deSUMOylation, thereby extending PD-L1 protein half-life. Importantly, SENP3 overexpression rescued the immunostimulatory effects of PD-L1 knockdown, confirming the specificity of this regulatory pathway. Our findings establish SENP3 as a novel posttranslational regulator of PD-L1 that promotes immune evasion in HCC through direct deSUMOylation and stabilization of PD-L1 protein. Therapeutic targeting of SENP3 may overcome resistance to immune checkpoint inhibitors in HCC by restoring antitumor immunity.
Ubiquitination mediated cisplatin resistance in bladder cancer.
Wang Y, Yuan J, Guo S … +2 more , Liu Y, Ma J
Anticancer Drugs · 2026 Jul · PMID 42008305 · Publisher ↗
Bladder cancer (BCa) patients frequently develop resistance to platinum-based therapies, particularly cisplatin. The link between chemoresistance and glycolysis has been well documented. Emerging evidence suggests that R...
Bladder cancer (BCa) patients frequently develop resistance to platinum-based therapies, particularly cisplatin. The link between chemoresistance and glycolysis has been well documented. Emerging evidence suggests that Rac family small GTPase 3 ( RAC3 ) may play significant roles in cisplatin resistance. This study investigated the underlying molecular mechanisms. Clinical specimens (cisplatin-sensitive/resistant BCa tissues and matched adjacent normal tissues) were collected from hospital. Cisplatin-resistant cell lines [T24-derived cisplatin-resistant cells (T24-DDP) and 5637-derived cisplatin-resistant cells (5637-DDP)] were generated through stepwise dose escalation. RAC3 , Myc-binding protein 2 (MYCBP2 ), P21-activated kinase 1 ( PAK1 ), Ki-67, and glycolysis markers were analyzed by quantitative PCR, immunohistochemistry, and Western blot. RAC3 ubiquitination was assessed via co-immunoprecipitation. Cell viability, apoptosis, and glycolytic metabolism were evaluated using the cell counting kit-8 assay, terminal deoxynucleotidyl transferase deoxyuridine triphosphate/flow cytometry, and ATP/lactate assays, respectively. Glycolytic flux was measured by extracellular acidification rate. Additionally, BCa xenograft models were established for in-vivo detection. Elevated RAC3 expression and glycolytic activity were observed in BCa tissues, with further augmentation in cisplatin-resistant tumors. RAC3 overexpression promoted cell viability, glycolysis, invasion, and migration in cisplatin-treated T24 and 5637 cells. Conversely, RAC3 knockdown exerted the opposite effects and restored cisplatin sensitivity in resistant T24-DDP and 5637-DDP cells. Notably, the sensitizing effect of RAC3 knockdown was reversed by PAK1 overexpression. Furthermore, MYCBP2 regulated RAC3 stability, as MYCBP2 overexpression enhanced RAC3 ubiquitination, suppressed glycolysis, and sensitized resistant cells to cisplatin. These effects were abrogated by the proteasome inhibitor MG132, confirming proteasome-dependent degradation of RAC3 . MYCBP2 -mediated ubiquitination of RAC3 modulates the PAK1 /pyruvate dehydrogenase E1 subunit alpha axis to regulate glycolytic activity, ultimately determining cisplatin sensitivity in BCa.
A novel HEAT repeat protein 5B anaplastic lymphoma kinase fusion in lung adenocarcinoma confers sensitivity to ensartinib.
Zhang G, Wu D, Deng H … +2 more , Xiao Q, Peng H
Anticancer Drugs · 2026 Mar · PMID 42003316 · Publisher ↗
Anaplastic lymphoma kinase (ALK) rearrangements are rare but highly actionable drivers in non-small cell lung cancer; however, uncommon fusion variants lack standard management. We report the clinical outcome of a novel...
Anaplastic lymphoma kinase (ALK) rearrangements are rare but highly actionable drivers in non-small cell lung cancer; however, uncommon fusion variants lack standard management. We report the clinical outcome of a novel HEAT repeat protein 5B (HEATR5B)-ALK fusion treated with ensartinib. A 52-year-old Chinese woman with stage IVA lung adenocarcinoma and left adrenal metastasis underwent tumor biopsy. Targeted DNA-based next-generation sequencing (NGS) identified HEATR5B(END..EX7)-ALK(IVS19..END) fusion; ALK protein expression was confirmed by immunohistochemistry (IHC). Ensartinib 225 mg orally once daily was initiated. Serial CT scans were evaluated according to RECIST 1.1; progression-free survival (PFS) and adverse events were recorded. The patient achieved a confirmed partial response at first restaging and maintained treatment for greater than 24 months without radiologic progression. No grade greater than or equal to 3 adverse events were observed; preexisting weight loss ceased. PFS is ongoing at the last follow-up (24+ months). The HEATR5B-ALK fusion is targetable by ensartinib, producing durable disease control and excellent tolerability. Comprehensive NGS and ALK IHC are essential for detecting rare actionable ALK variants.
3-Aminoisoquinolines inhibit selectively phosphodiesterase 4B in KRAS-mutated colorectal cancer cell lines in-vitro and in-vivo.
Lapa GB, Tsunoda T, Moiseeva NI
Anticancer Drugs · 2026 Mar · PMID 41934673 · Publisher ↗
Phosphodiesterase 4B (PDE4B), an isoform of cyclic nucleotide phosphodiesterases, is integrated into cell membranes and hydrolyzes cyclic AMP in specific cellular compartments. Overexpression of PDE4B has been observed i...
Phosphodiesterase 4B (PDE4B), an isoform of cyclic nucleotide phosphodiesterases, is integrated into cell membranes and hydrolyzes cyclic AMP in specific cellular compartments. Overexpression of PDE4B has been observed in hematological and gastrointestinal tumors harboring KRAS mutations, leading to the disruption of cell cycle regulation. Utilizing molecular docking, we identified 3-aminoisoquinolines as potential selective PDE4B inhibitors. Phenotypic screening on HKe3-KRAS cell lines confirmed that PDE4B is a selective target for these novel 3-aminoisoquinolines. We employed molecular docking and calculated ligand efficiency as predictive tools for methylthiazoltetrazolium assay activity to reduce the combinatorial library size. Six active compounds (047, 048, 086, 089, 091, and 099) were screened. Active compounds 047, 048, 086, 089, and 091 demonstrated selectivity toward HKe3-mtKRAS over wild-type cells. This 'synthetic lethality-like' approach was effective in predicting the anticancer properties of these compounds in KRAS-mutated cell lines. NCI-DTP 60 cell lines assays confirmed the activities of 047, 048, and 089. Compound 089 showed strong cytotoxicity against HCT-116 cells inhibitory concentration (IC50) = 1.6 μM, growth inhibition (GI50) = 0.53 μM, and an inhibitory concentration (IC50) against PDE4B = 2.5 μM. In addition, 089 exhibited good tolerability in a nude mouse HCT-116 xenograft model, but it was less effective at a dose of 40 mg/kg compared with Apremilast at a dose of 30 mg/kg in 8-s day's assay. While 089 had lower in-vivo efficacy than apremilast, its novel 3-aminoisoquinoline scaffold and high tolerability make it a superior candidate for further optimization.
Envafolimab combined with chemotherapy in advanced thymic carcinoma - first clinical experience with a novel subcutaneous programmed death-ligand 1 inhibitor.
Sun W, Wan H
Anticancer Drugs · 2026 Mar · PMID 41903690 · Publisher ↗
Thymic carcinoma is rare with poor prognosis, and novel treatments are needed. We report two cases of advanced thymic carcinoma treated with the programmed death-ligand 1 inhibitor envafolimab with chemotherapy (liposoma...
Thymic carcinoma is rare with poor prognosis, and novel treatments are needed. We report two cases of advanced thymic carcinoma treated with the programmed death-ligand 1 inhibitor envafolimab with chemotherapy (liposomal paclitaxel and cisplatin). Case 1: A 59-year-old woman with metastatic thymic carcinoma (suspected neuroendocrine carcinoma) involving liver and bone received radiotherapy for spinal metastasis followed by eight cycles of envafolimab with liposomal paclitaxel and cisplatin. She achieved a partial tumor response with lesion shrinkage and normalization of liver function and tumor markers without grade 3 or higher adverse events, but later developed disease progression with anterior mediastinal mass enlargement, new left lung metastasis, bilateral pleural effusion, ascites, and pelvic effusion. Because of rapid disease progression and intolerance to further antitumor therapy, the patient died in May 2025. Her progression-free survival (PFS) was 6 months and overall survival was 10 months. Case 2: A 69-year-old man with metastatic thymic squamous carcinoma and multiple comorbidities was treated with definitive radiotherapy to the mediastinal tumor and eight cycles of envafolimab with chemotherapy. He achieved a complete response with tumor reduction and normalized markers. Treatment was well-tolerated without grade 3 or higher adverse events. As of the latest follow-up, PFS was 9 months, and he continues maintenance envafolimab with good tolerance. Both patients achieved PFS (6 and 9 months, respectively) that exceeded the median PFS reported in previous clinical studies using chemotherapy alone (5 months). This combination warrants further investigation in clinical trials.
Case report: successful use of repotrectinib in a ROS1 fusion-positive lung adenocarcinoma patient with severe renal insufficiency and prior tyrosine kinase inhibitor treatment failure.
Liang Z, Li H
Anticancer Drugs · 2026 Mar · PMID 41903327 · Publisher ↗
During sequential targeted therapy for ROS1 fusion-positive non-small cell lung cancer, some patients may develop severe renal insufficiency due to drug-related adverse events, resulting in limited subsequent treatment o...
During sequential targeted therapy for ROS1 fusion-positive non-small cell lung cancer, some patients may develop severe renal insufficiency due to drug-related adverse events, resulting in limited subsequent treatment options with uncertain efficacy. We report a case of a 69-year-old female patient with advanced lung adenocarcinoma harboring an SDC4-ROS1 fusion mutation. Imaging revealed multiple nodules and masses in both lungs, enlarged mediastinal lymph nodes, and bilateral pleural effusion. The patient received treatment with crizotinib and entrectinib successively. During this period, the patient experienced renal hemorrhage and developed renal cysts and renal atrophy. Laboratory findings revealed persistently elevated serum creatinine levels and a significant decline in estimated glomerular filtration rate. She ultimately developed severe renal insufficiency, concurrent with tumor progression. Repotrectinib therapy was initiated based on tumor progression and renal function status under close monitoring, and an objective response occurred in this patient. Moreover, the serum creatinine levels decreased and remained relatively stable, indicating improved renal function. No new severe drug-related adverse events were observed. This case suggests that in patients with ROS1 fusion-positive nonsmall cell lung cancer who have experienced prior ROS1-tyrosine kinase inhibitor treatment failure and concomitant severe renal insufficiency, repotrectinib may represent a potential and tolerable treatment option when fully assessing clinical risks and ensuring close monitoring.
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