Molecular Cancer Therapeutics最新文献

{"title":"PLK4 Inhibition as a Strategy to Enhance Non-Small Cell Lung Cancer Radiosensitivity.","authors":"Irma G Domínguez-Vigil, Kishore Banik, Marta Baro, Joseph N Contessa, Thomas J Hayman","doi":"10.1158/1535-7163.MCT-24-0978","DOIUrl":"10.1158/1535-7163.MCT-24-0978","url":null,"abstract":"<p><p>Lung cancer is the leading cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer and comprises 85% of cases. Despite treatment advances, local control after curative-intent chemoradiation for NSCLC remains suboptimal. Polo-like kinase 4 (PLK4) is a serine-threonine kinase that plays a critical role in the regulation of centrosome duplication and cell-cycle progression and is overexpressed in NSCLC, thus making it a potential therapeutic target. CFI-400945 is an orally available PLK4 inhibitor currently undergoing clinical trial evaluation. As radiation causes cell death primarily by mitotic catastrophe, a process enhanced by alterations in centrosome amplification, we hypothesized that disruption of the mitotic machinery by inhibition of PLK4 would enhance the effects of radiation in NSCLC. PLK4 inhibition by CFI-400945 resulted in radiosensitization of NSCLC cell lines. In contrast, CFI-400945 had no effect on the radiosensitivity of normal lung fibroblasts. PLK4 inhibition did not affect cell-cycle phase distribution prior to radiation, but rather the combination of CFI-400945 and radiation resulted in increased G2/M cell-cycle arrest, increased centrosome amplification, and a concomitant increase in cell death through mitotic catastrophe. Lastly, CFI-400945 treatment enhanced the radiation-induced tumor growth delay of NSCLC tumor xenografts. These data indicate that targeting PLK4 is a novel approach to enhance the radiation sensitivity of NSCLC in vitro and in vivo through potentiation of centrosome amplification and cell death through mitotic catastrophe.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1350-1361"},"PeriodicalIF":5.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12353405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"6-[(1,4-Naphthoquinone-2-yl)methyl]thio-Glucose Conjugates, a Novel Targeted Approach for Advanced Prostate Cancer.","authors":"Tobias Busenbender, Dmitry N Pelageev, Jessica Hauschild, Moritz Kaune, Lukas Boeckelmann, Christoph Krisp, Mohamed E Elsesy, Alexandra Zielinski, Thomas Mair, Maria Riedner, Ayham Moustafa, Simone Venz, Malte Kriegs, Konstantin Hoffer, Yuri E Sabutski, Ksenia L Borisova, Nadja Strewinsky, Svetlana M Kovach, Ekaterina A Khmelevskaya, Hartmut Schlüter, Victor Ph Anufriev, Derya Tilki, Markus Graefen, Wael Y Mansour, Carsten Bokemeyer, Sergey A Dyshlovoy, Gunhild von Amsberg","doi":"10.1158/1535-7163.MCT-24-0955","DOIUrl":"10.1158/1535-7163.MCT-24-0955","url":null,"abstract":"<p><p>The Warburg effect is a shift from oxidative phosphorylation to anaerobic glycolysis, accompanied by an enormous increase in glucose uptake into cancer cells. We have utilized this effect to design a new group of targeted 1,4-naphthoquinone-glucose derivatives conjugated with a novel thiomethylene linker that are cytotoxic to prostate cancer cells. Compound PeS-9 revealed the highest efficacy and selectivity, which was conditioned by a GLUT-1-mediated uptake. PeS-9 induced androgen receptor degradation followed by downregulation of its signaling. In addition, it increased reactive oxygen species production and induced DNA double-strand breaks. Combinational therapy with PARP inhibitor olaparib resulted in synergistic effects in homologous recombination-deficient cells. The underlying mode of PeS-9's cytotoxic action involved mitochondrial targeting, leading to a loss of mitochondrial membrane potential, release of cytochrome C and apoptosis-inducing factor, activation of caspases-3 and -9, PARP cleavage, and apoptotic cell death. This process was stipulated by downregulation of several antiapoptotic factors and induction of endoplasmic reticulum stress. Moreover, drug-induced activation of signaling pathway mediated by p38, JNK1/2, and ERK1/2 kinases was identified as an important factor of the cytotoxic activity. The anticancer activity of PeS-9 could be confirmed ex vivo using patient-derived tumoroids as well as in vivo in xenografts, demonstrating suppression of tumor growth and decreased dissemination of prostate cancer cells to the lungs. No serious side effects were observed in animal models. This unique combination of anticancer properties makes PeS-9 an attractive candidate for targeted monotherapy against GLUT-1-overexpressing tumors and as a potential combination partner, especially with PARP inhibitors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1331-1349"},"PeriodicalIF":5.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Chimeric CTLA-4 B-cell Epitope Peptide Vaccines Demonstrate Effective Antitumor Immunity with/without PD1/PDL1 Blockade in Multiple Syngeneic Murine Models of Breast and Colorectal Cancers.","authors":"Linlin Guo, Jay Overholser, Sarah Naylon, Stephane Roche, Nicholas Ede, Pravin T P Kaumaya","doi":"10.1158/1535-7163.MCT-24-0908","DOIUrl":"10.1158/1535-7163.MCT-24-0908","url":null,"abstract":"<p><p>Cancer immunotherapy with checkpoint inhibitors has resulted in impressive clinical results in several cancer indications. Despite this success, only a fraction of patients show durable and complete response to blockade by ipilimumab, an anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) mAb. We identified four CTLA-4 peptide sequences from which engineered chimeric B-cell epitope constructs incorporating a \"promiscuous\" T-cell epitope elicited highly immunogenic anti-CTLA-4 natural polyclonal antibodies by immunization. Combination of CTLA-4 peptide vaccine with other checkpoint inhibitor vaccines PD1-Vaxx or PDL1-Vaxx was investigated in several breast and colon carcinoma BALB/c syngeneic models (CT26, 4T1, and D2F2). CTLA-4 vaccines showed significant tumor suppression and prolonged survival rates as compared with anti-mouse CTLA-4 mAb 9H10. The resulting antipeptide antibodies suppressed tumor proliferation and migration similar to ipilimumab. We focused on one CTLA-4 epitope sequence 130 to 150 that embodies the \"MYPPPY\" motif that ipilimumab binds to. Combination of MVF-CTLA-4 (130-150) with either PD1-Vaxx or PDL1-Vaxx showed synergistic activity. The 130 to 150 peptide mimic demonstrated that the polyproline type II helix motif showed inhibition of tumor growth and therapeutic efficacy in the syngeneic CT26/BALB/c model. Several CTLA-4 vaccines have been identified that show synergistic activities with other checkpoint inhibitor vaccines to PD1 and PDL1.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1362-1377"},"PeriodicalIF":5.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12402803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144001847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SHR-2005, an FcγR-Dependent CD40 Agonistic Antibody with Potent Antitumor Activities and Favorable Safety Profile.","authors":"Li-Min Wang, Changyong Yang, Xing Sun, Yunan Tian, Jieqiong Zhang, Xue Wang, Lei Zhou, Zhijun Wang, Yuan Lin, Tingting Wu, Wei Zhang, Jiayi Li, Cheng Liao","doi":"10.1158/1535-7163.MCT-24-0999","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0999","url":null,"abstract":"<p><p>Activation of CD40, a pivotal component of immune oncology, could facilitate the infiltration of immune cells into the tumor microenvironment. In this investigation, we characterized SHR-2005, a second-generation CD40 agonistic mAb, as a potential candidate for cancer immune therapy. Our results showed that SHR-2005 possessed high affinity in binding to both human and rhesus CD40 and could effectively compete with CD40L for CD40 binding. Notably, SHR-2005 was engineered to exert a strong affinity for human FcγRIIb, consistent with its observed Fc receptor-dependent agonistic activity. Treatment with SHR-2005 led to robust activation of the CD40 signaling pathway and subsequent immune response. The murine surrogate SHR-2005-mIgG1 exhibited potent inhibition of tumor growth in the MC38 allograft model and showed enhanced antitumor efficacy in combination with the anti-PD-L1 antibody. Furthermore, intravesical instillation of SHR-2005-mIgG1 also increased the populations of dendritic cells (DC), CD3+ T cells, and CD4+ T cells in bladder tissue. No obvious abnormality except for a reversible local irritation was observed via intravesical instillation. Notably, SHR-2005 induced significantly lower IL-6 secretion than the APX005M analogue in human peripheral blood mononuclear cells, indicating a favorable safety profile. In conclusion, the CD40 agonistic antibody SHR-2005 was highly reliant on FcγR for agonistic activation and exhibited promising potential for clinical development as monotherapy or in combination with the anti-PD-L1 antibody for the treatment of solid tumors. Based on promising efficacy and tolerance in preclinical studies, SHR-2005 is currently being evaluated in an ongoing phase I clinical trial for the intravesical treatment of high-risk non-muscle-invasive bladder cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF14"},"PeriodicalIF":5.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical characterization of XB010: a novel antibody-drug conjugate for the treatment of solid tumors that targets tumor-associated antigen 5T4.","authors":"Brian A Mendelsohn, Kathleen R Gogas, Jeffrey N Higaki, Willy A Solis, Inna Vainshtein, Jackie Cheng, Minjong Park, Marlene A Hennessy, Christine M Janson, Yutaka Matsuda, Robyn M Barfield, Penelope M Drake, Stepan Chuprakov, Colin L Hickle, Tom Linz, Maxine Bauzon, Dominick Y Yeo, Fangjiu Zhang, Ayodele O Ogunkoya, Seema Kantak","doi":"10.1158/1535-7163.MCT-24-1014","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-1014","url":null,"abstract":"<p><p>The oncofetal antigen 5T4 is expressed in many solid tumors, making it an attractive anti-tumor target. XB010 is a novel, 5T4-targeted, antibody-drug conjugate (ADC) developed using the SMARTag® platform to optimize tolerability. We describe the development, design, and preclinical characterization of XB010. In vitro and in vivo efficacy of XB010 was assessed in cell-derived xenograft breast cancer cell lines (MCF-7 and MDA-MB-468) and in patient-derived xenograft (PDX) tumor models (squamous cell carcinoma of the head and neck, non-small cell lung cancer, and breast cancer). Additionally, the in vivo combinatorial efficacy of XB010 + anti-programmed cell death protein 1 (anti-PD-1) antibody was assessed in an MC38-h5T4 syngeneic colon cancer xenograft model. The toxicity profile of XB010 was evaluated in both Sprague Dawley rats and cynomolgus monkeys. XB010 demonstrated in vitro cytotoxic effects with sub-nanomolar potency in the MCF-7 and MDA-MB-468 breast cancer cell lines and in vivo tumor growth inhibition (80%-99%) compared with vehicle-treated animals in xenograft and PDX models at doses of 5-10 mg/kg XB010. In the syngeneic MC38-h5T4 expressing colon cancer xenograft model, XB010 + anti-PD-1 showed improved efficacy compared with either agent administered alone. XB010 safety assessments demonstrated tolerability of doses up to 60 mg/kg in rats and up to 25 mg/kg in non-human primates. XB010 is a novel anti-5T4 ADC that exhibits potent anti-tumor activity, inhibiting cancer cell growth in vitro and tumor growth in various in vivo models, with an acceptable toxicity profile. These findings support the evaluation of XB010 in clinical studies.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined Inactivation of MEK and mTOR Can Lead to Synergistic Cell Death in Glioblastoma Models and Associates with NF1 Deficiency and a Mesenchymal Subtype.","authors":"Fleur M G Cornelissen, Yoran Broersma, Ravi S Narayan, Rogier Dik, Sander R Piersma, Richard de Goeij-de Haas, Thang V Pham, David Noske, William P Vandertop, Connie R Jimenez, Bart A Westerman","doi":"10.1158/1535-7163.MCT-23-0864","DOIUrl":"10.1158/1535-7163.MCT-23-0864","url":null,"abstract":"<p><p>Glioblastoma (GB) is the most common and aggressive brain-derived tumor. It often shows genetic alterations in kinase signaling pathways, such as the Pi3K/mTOR and RAS/MAPK pathways, which frequently converge onto oncogenic processes. However, it is unknown to what extend co-vulnerabilities exist within this network and which kinase drug targets are promising for GB treatment. We investigated the drug sensitivity of GB cell line models to monotherapy and synergy effects in dual combination therapy to targeting components of Pi3K/mTOR and RAS/MAPK pathways. In addition, we examined cell line drug sensitivities in relation to their individual genetic tumor-driving lesions [i.e., neurofibromin 1 (NF1) alterations as well as transcriptomic defined GB subtypes]. Synergy levels were correlated to in-lab generated phosphoproteomic data. Lastly, serial or simultaneous addition of MEK and mTOR inhibitors was investigated in longitudinal experiments. Dual inhibition of MEK and mTOR resulted in synergistic effects, which were associated with NF1 deficiency. Strong synergy effects were also associated with the mesenchymal subtype. Dual inhibition of MEK and mTOR led to prolonged growth inhibition in GB spheroids. In addition, sequential drug treatment resulted in similar growth inhibitory effects compared with simultaneous combination therapies. Our findings highlight the potential of dual inhibition strategies targeting multiple kinases for the treatment of GB, particularly in NF1-deficient and mesenchymal tumors, the most lethal subtype of GB.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF12"},"PeriodicalIF":5.5,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of Siglec-15 in tumor immunity: mechanism and therapy.","authors":"Lin Li, Li Wang, Qin Liu, Yingchun Ye, Qian Lei, Chengwen Li, Xiyuan Guo, Siji Nian, Qing Yuan","doi":"10.1158/1535-7163.MCT-25-0323","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0323","url":null,"abstract":"<p><p>Siglec-15, a member of the sialic acid-binding immunoglobulin-like lectins (Siglecs) family, has emerged as a pivotal immunosuppressive mediator and a promising therapeutic target in cancer immunotherapy. This transmembrane glycoprotein orchestrates multifaceted biological processes, such as osteoclastogenesis regulation, bone remodeling, and tumor-associated macrophage (TAM)-mediated T cell immunosuppression. Notably, Siglec-15 exhibits non-redundant expression with programmed death-ligand 1 (PD-L1), suggesting its compensatory role in immune evasion mechanisms within PD-L1-negative tumor microenvironment (TME). This review delineates the molecular architecture of Siglec-15 and elucidates its pleiotropic regulatory mechanisms. Particular emphasis is placed on deciphering its immunomodulatory functions within tumor ecosystems, while critically evaluating emerging therapeutic modalities targeting Siglec-15, spanning from preclinical validation to ongoing clinical trials.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Vivo Tumor Growth Control by General Control Nonderepressible 2 Targeting Agents Results from Kinase Activation.","authors":"Feven Tameire, Paulina Wojnarowicz, Crissy Dudgeon, Kathryn T Bieging-Rolett, Sho Fujisawa, Savi Ramurthy, Owen Reilly, Christopher G Thomson, Bradley S Sherborne, Simon J Taylor, Fang He, Pengwei Pan, Baozhong Li, Earl May, Alan C Rigby, Mark J Mulvihill, Nandita Bose, David Surguladze, Eric S Lightcap","doi":"10.1158/1535-7163.MCT-24-0960","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0960","url":null,"abstract":"<p><p>General Control Nonderepressible 2 (GCN2; EIF2AK4) is a serine-threonine kinase in the integrated stress response (ISR) signaling pathway that initiates adaptive responses during nutrient stress conditions. While pharmacological inhibition of GCN2 under nutrient stress conditions induces apoptosis and inhibits tumor growth, GCN2 inhibition without nutrient stress has been reported to have no effect on tumor growth. By exploring an array of GCN2 inhibitors, we demonstrate that multiple agents in fact activate GCN2 in biochemical and cell-based assays at low concentrations and inhibit GCN2 at higher concentrations. Unexpectedly, it is this activation, and not inhibition, of the GCN2 pathway that is associated with decreased viability in vitro and tumor growth inhibition in vivo across multiple models. Knockdown and knockout experiments show that activation of the ISR by GCN2-targeting agents is dependent on GCN2. ISRIB, a modulator of eIF2B, ablates the viability effect, demonstrating the dependence on translation initiation. Activating doses result in the induction of cleaved caspase 3 and cleaved PARP. In contrast, a nonactivating GCN2-targeting agent does not impact viability. These results provide a clearer understanding of the challenges and opportunities for the clinical development of compounds targeting GCN2.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TUB-010, a novel anti-CD30 antibody-drug conjugate based on Tub-tag technology, widens the therapeutic window by reducing toxicity while maintaining high efficacy.","authors":"Marcus Gerlach, Saskia Schmitt, Philipp Cyprys, Marc-André Kasper, Isabelle Mai, Magdalena Klanova, Andreas Maiser, Heinrich Leonhardt, Christian P R Hackenberger, Günter R Fingerle-Rowson, Annette M Vogl, Dominik Schumacher, Jonas Helma","doi":"10.1158/1535-7163.MCT-25-0062","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0062","url":null,"abstract":"<p><p>TUB-010 is a next-generation antibody-drug conjugate (ADC) targeting CD30 expressed on various hematopoietic malignancies such as Hodgkin lymphoma. Among the therapeutic options for patients with relapsed and refractory CD30-positive cancers is brentuximab vedotin (Adcetris), an MMAE-delivering anti-CD30 ADC with a mean drug-to antibody ratio (DAR) of 4. Adcetris exhibits a high response rate at the cost of significant toxicities, likely driven by the payload MMAE and instability of the maleimide conjugation chemistry. TUB-010 uses the same antibody and payload as Adcetris, but is based on the Tub-tag conjugation strategy, which stably attaches MMAE to the hydrophilic Tub-tag peptides on the light chains via chemoenzymatic conjugation. This new technology enables the generation of a homogenous and site-specific DAR 2 ADC with unique biophysical properties. TUB-010 demonstrates similar binding and lysosomal release characteristics as Adcetris, which translates into comparable in vitro cytotoxicity on CD30-positive cell lines when normalized to the MMAE concentration. Importantly, TUB-010 exhibits higher stability with neglectable premature deconjugation in circulation and reduced aggregation as well as lower non-specific cytotoxicity on target-negative cells compared to Adcetris. As a consequence, TUB-010 induces superior tumor control compared to Adcetris when dosed at equal MMAE concentrations in vivo and also lower toxicity and higher tolerability in rodents and non-human primates. Taken together, TUB-010 is a novel, potential best-in-class anti-CD30 ADC with improved biophysical properties designed to deliver MMAE with higher precision and a wider therapeutic window than Adcetris using Tub-tag technology. Therefore, TUB-010 may increase the clinical benefit of anti-CD30 ADC therapies.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Co-Targeting Bcl-xL with Mcl-1 Induces Lethal Mitochondrial Dysfunction in Diffuse Mesothelioma.","authors":"R Taylor Ripley, Yuan Xu, Cristian G Medina, Deborah R Surman, Lacey E Dobrolecki, Monica Vilchis, Maheshwari Ramineni, Susan G Hilsenbeck, Yanming Li, Naren Li, Siqi Wu, Jaylon C Aggison, Xi Chen, Yi Zhu, Ying H Shen","doi":"10.1158/1535-7163.MCT-24-0873","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0873","url":null,"abstract":"<p><p>Diffuse mesothelioma (DM) is a rare but highly aggressive and treatment resistant neoplasm with low survival rates. Effective therapeutic strategies are limited, and resistance to treatment is a major obstacle. Myeloid Cell Leukemia (MCL)-1 and B-cell leukemia (BCL)-xL are anti-apoptotic B-cell lymphoma 2 (Bcl-2) family proteins that block cell-intrinsic apoptosis through interactions on the mitochondrial outer membrane which contribute to therapeutic resistance. We investigated whether B-cell homology domain (BH)-3 profiles were consistent between intra-patient fresh tumor sample, patient-derived cells (PDC), and patient-derived xenografts (PDX) by BH3 profiling; we observed striking consistency which enabled cross model comparisons. Next, we co-targeted BCL-xl and MCL-1 and noted that the combination synergistically reduced cell viability and increased apoptosis. Mechanistically, BCL-xL inhibition affected the cells through both the canonical and the emerging non-canonical apoptotic pathways. BCL-xL induced mitochondrial depolarization which resulted in MCL-1 cellular dependency rendering cells highly sensitive to MCL-1 inhibition. Next, we co-targeted BCL-xL and MCL-1 in vivo which induced synthetic lethality in PDX models within hours, implying that this approach is not a safe strategy for clinical development. However, targeting MCL-1, which exerts its anti-apoptotic activity without non-apoptotic on-target effects, decreased the mitochondrial threshold for apoptosis and enhanced chemosensitivity without toxicity in PDX models. Our findings suggest that targeting the mitochondria via MCL-1 enhances the efficacy of chemotherapy but co-targeting two proteins in the Bcl-2 pathways results in synergistic lethality. These results will help define a safe clinical strategy to utilize Bcl-2 targeted therapy to undermine therapeutic resistance in patients with DM.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144847580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}