Molecular Cancer Therapeutics最新文献

{"title":"Characterization of TNG348: A Selective, Allosteric USP1 Inhibitor That Synergizes with PARP Inhibitors in Tumors with Homologous Recombination Deficiency.","authors":"Antoine Simoneau, Charlotte B Pratt, Hsin-Jung Wu, Shreya S Rajeswaran, Charlotte Grace Comer, Sirimas Sudsakorn, Wenhai Zhang, Shangtao Liu, Samuel R Meier, Ashley H Choi, Tenzing Khendu, Hannah Stowe, Binzhang Shen, Douglas A Whittington, Yingnan Chen, Yi Yu, William D Mallender, Tianshu Feng, Jannik N Andersen, John P Maxwell, Scott Throner","doi":"10.1158/1535-7163.MCT-24-0515","DOIUrl":"10.1158/1535-7163.MCT-24-0515","url":null,"abstract":"<p><p>Inhibition of the deubiquitinating enzyme USP1 can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD) and represents a novel therapeutic strategy for the treatment of BRCA1/2-mutant cancers, potentially including patients whose tumors have primary or acquired resistance to PARP inhibitors (PARPi). In this study, we present a comprehensive characterization of TNG348, an allosteric, selective, and reversible inhibitor of USP1. TNG348 induces dose-dependent accumulation of ubiquitinated protein substrates both in vitro and in vivo. CRISPR screens show that TNG348 exerts its antitumor effect by disrupting the translesion synthesis pathway of DNA damage tolerance through RAD18-dependent ubiquitinated PCNA. Although TNG348 and PARPi share the ability to selectively kill HRD tumor cells, CRISPR screens reveal that TNG348 and PARPi do so through discrete mechanisms. Particularly, knocking out PARP1 causes resistance to PARPi but sensitizes cells to TNG348 treatment. Consistent with these findings, combination of TNG348 with PARPi leads to synergistic antitumor effects in HRD tumors, resulting in tumor growth inhibition and regression in multiple mouse xenograft tumor models. Importantly, our data on human cancer models further show that the addition of TNG348 to PARPi treatment can overcome acquired PARPi resistance in vivo. Although the clinical development of TNG348 has been discontinued because of unexpected liver toxicity in patients (NCT06065059), the present data provide preclinical and mechanistic support for the continued exploration of USP1 as a drug target for the treatment of patients with BRCA1/2-mutant or HRD cancers.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"678-691"},"PeriodicalIF":5.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066696","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":"Ultrahigh Dose Rate Helium Ion Beams: Minimizing Brain Tissue Damage while Preserving Tumor Control.","authors":"Ivana Dokic, Mahmoud Moustafa, Thomas Tessonnier, Sarah Meister, Federica Ciamarone, Mahdi Akbarpour, Damir Krunic, Thomas Haberer, Jürgen Debus, Andrea Mairani, Amir Abdollahi","doi":"10.1158/1535-7163.MCT-24-0536","DOIUrl":"10.1158/1535-7163.MCT-24-0536","url":null,"abstract":"<p><p>Ultrahigh dose rate radiotherapy (RT) with electrons and protons has shown potential for cancer treatment by effectively targeting tumors while sparing healthy tissues (FLASH effect). This study aimed to investigate the potential FLASH sparing effect of ultrahigh dose rate helium ion irradiation, focusing on acute brain injury and subcutaneous tumor response in a preclinical in vivo setting. Raster-scanned helium ion beams were used to compare the effects of standard dose rate (SDR; at 0.2 Gy/second) and FLASH (at 141 Gy/second) RT on healthy brain tissue. Irradiation-induced brain injury was studied in C57BL/6 mice via DNA damage response, using nuclear γH2AX as a marker for double-strand breaks. The integrity of neurovascular and immune compartments was assessed through CD31+ microvascular density and activation of microglia/macrophages. IBA1+ ramified and CD68+ phagocytic microglia/macrophages were quantified, along with the expression of inducible nitric oxide synthetase. Tumor response to SDR (0.2 Gy/second) and FLASH (250 Gy/second) RT was evaluated in an A549 carcinoma model, using tumor volume and Kaplan-Meier survival as endpoints. The results showed that helium FLASH RT significantly reduced acute brain tissue injury compared with SDR, evidenced by lower levels of double-strand breaks and preserved the neurovascular endothelium. Additionally, FLASH RT reduced neuroinflammatory signals compared with SDR, as indicated by fewer CD68+ inducible nitric oxide synthetase-positive microglia/macrophages. FLASH RT achieved tumor control comparable with that of SDR RT. To the best of our knowledge, this is the first study to report the FLASH sparing effect of raster scanning helium ion RT in vivo, highlighting its potential for neuroprotection and effective tumor control.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"763-771"},"PeriodicalIF":5.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909990","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":"Heterogeneous Responses to High-Dose Testosterone in Castration-Resistant Prostate Cancer Tumors with Mixed Rb-Proficient and Rb-Deficient Cells.","authors":"Maryam Labaf, Wanting Han, Songqi Zhang, Mingyu Liu, Nolan D Patten, Muqing Li, Susan Patalano, Jill A Macoska, Steven P Balk, Dong Han, Kourosh Zarringhalam, Changmeng Cai","doi":"10.1158/1535-7163.MCT-24-0716","DOIUrl":"10.1158/1535-7163.MCT-24-0716","url":null,"abstract":"<p><p>Androgen deprivation therapy remains a cornerstone in managing prostate cancer. However, its recurrence often leads to the more aggressive castration-resistant prostate cancer (CRPC). Although second-line androgen receptor signaling inhibition treatments such as enzalutamide and abiraterone are available, their effectiveness against CRPC is only transient. High-dose testosterone (Hi-T) has recently emerged as a promising treatment for CRPC, primarily through the suppression of E2F and MYC signaling. However, the roles of Rb family proteins in influencing this therapeutic response remain debated. In this study, we utilized a CRPC patient-derived xenograft model that includes both Rb pathway-proficient and -deficient cell populations based on the positive or negative expression of RB family genes. Single-cell RNA sequencing analysis revealed that Rb-proficient cells displayed a robust response to Hi-T, whereas Rb-deficient cells exhibited significant resistance. Notably, our analysis indicated increased enrichment of the hypoxia signature in the Rb-deficient cell population. Further studies in RB1-silenced CRPC cell lines showed that treatment with a hypoxia-inducible factor-1α inhibitor can restore the sensitivity of Rb-deficient cells to high-dose dihydrotestosterone treatment. In conclusion, our research provides new molecular insights into CRPC tumor cell responses to Hi-T and proposes a new strategy to resensitize Rb-deficient CRPC cells to Hi-T treatment.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"772-783"},"PeriodicalIF":5.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673367","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":"First-in-Human Study of ABY-029, a Novel Fluorescent Peptide that Targets EGFR, Applied to Soft-Tissue Sarcomas.","authors":"Kimberley S Samkoe, Hira Shahzad Sardar, Jason R Gunn, Jonathan Thomas Elliott, Sally Mansur, Joachim Feldwisch, Brian W Pogue, Konstantinos Linos, Keith D Paulsen, Eric R Henderson","doi":"10.1158/1535-7163.MCT-24-0378","DOIUrl":"10.1158/1535-7163.MCT-24-0378","url":null,"abstract":"<p><p>ABY-029, an anti-EGFR Affibody molecule conjugated to IRDye 800CW, recently underwent first-in-human testing in soft-tissue sarcoma. The FDA Exploratory Investigational New Drug status was obtained for the phase 0 clinical trial in which study objectives were to determine whether a biological variance ratio (BVR) of 10 was achievable, whether fluorescence intensity correlated with EGFR expression, and whether doses were well tolerated. Patients (N = 12) with soft-tissue sarcoma were recruited based on positive EGFR IHC staining of diagnostic biopsies. ABY-029 was administered at a microdose (30 nmol, n = 3), medium dose (90 nmol, n = 3), or high dose (171 nmol, n = 6) 1 to 3 hours prior to surgery. Following tumor resection, ex vivo tissue was imaged to determine the mean fluorescence intensity, BVR, and other contrast measures. EGFR expression was correlated with IHC. For micro, medium, and high doses, mean BVR (SD) values in cross-sectional slices were 4 (4), 10 (6), and 7 (8) for the whole tumor region and 6 (5), 13 (11), and 8 (6) for pathology-confirmed regions of interest, respectively. Strong linear correlations were found between all ABY-029 contrast metrics and total EGFR (r≥ 0.86; P < 0.029) in cross-sectional tissue slices and between mean fluorescence intensity and EGFR percent area (r = 0.63; P < 0.0001) in excised region-of-interest tissue sections. No ABY-029-related adverse events were observed. When administered above the microdose, ABY-029 demonstrated a high correlation with EGFR expression and contrast values that were encouraging for translation to clinical practice. Contrast values were similar to those observed with antibody agents but with a substantially reduced imaging-to-resection time and no drug-related adverse events.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"784-795"},"PeriodicalIF":5.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142837757","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":"Mechanisms of Response and Resistance to PSMA×CD3 Bispecifics in CD34+ Humanized Mice.","authors":"Bethany K Mattson Cypert, Krista Menard, Gerald Chu, Theresa McDevitt, Raluca I Verona, Brent Rupnow, Kathryn Packman","doi":"10.1158/1535-7163.MCT-23-0779","DOIUrl":"10.1158/1535-7163.MCT-23-0779","url":null,"abstract":"<p><p>Prostate cancer is considered immunologically \"cold,\" with low mutational burden, tumor-infiltrating immune cells, and PD-L1 levels, culminating in poor response to immune checkpoint therapies. CD3 bispecific redirection antibodies can elicit T cell-mediated cytotoxicity and hold promise for immune cell recruitment into prostate tumors. CD3 redirection antibodies in solid tumors are still in the early phases of clinical development, and it is not yet understood whether these potential therapies will achieve the high response rates observed in hematologic malignancies or result in durable T-cell responses. In this study, we demonstrated that treatment with a prostate-specific membrane antigen (PSMA)-targeted CD3 redirector resulted in efficacy against LnCaP.AR human prostate xenografts in CD34+ cord blood-humanized mice. Efficacy correlated with T-cell infiltration into tumors with an activated phenotype and also increased PD-L1 expression. Engineered overexpression of PD-L1 in LNCaP.AR tumors resulted in resistance to PSMA×CD3 bispecific antibody treatment, whereas sensitivity was restored in combination with anti-PD-1 antibody pembrolizumab. PSMA×CD3 and anti-PD-1 combination treatment resulted in complete tumor responses in approximately 20% of mice and elicited immune responses that delayed growth of rechallenged tumors. In a second prostate model, patient-derived LuCaP 86.2 xenografts, PSMA×CD3 monotherapy treatment resulted in complete responses in 25% of mice. When PSMA×CD3-treated responder mice were rechallenged with LuCaP 86.2 tumors, partial control of tumor regrowth was associated with the expansion of effector memory T cells. These studies show that PSMA×CD3 treatment elicits antitumor memory T-cell responses and that combination with PD-1 blockade can enhance these effects in tumors with immune-suppressive tumor microenvironments.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"740-752"},"PeriodicalIF":5.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143502675","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-blocking TIGIT and PVRIG Using a Novel Bispecific Antibody Enhances Antitumor Immunity.","authors":"Yuan Lin, Kan Lin, Qiang Fu, Xing Sun, Huan Wang, Lu Su, Yanhui Xu, Cheng Liao","doi":"10.1158/1535-7163.MCT-23-0614","DOIUrl":"10.1158/1535-7163.MCT-23-0614","url":null,"abstract":"<p><p>T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) and poliovirus receptor-related immunoglobulin domain (PVRIG) are immune checkpoints co-expressed on activated T and NK cells, contributing to tumor immune evasion. Simultaneous blockade of these pathways may enhance therapeutic efficacy, positioning them as promising dual targets for cancer immunotherapy. This study aimed to develop a bispecific antibody (BsAb) to co-target TIGIT and PVRIG. Expression of TIGIT and PVRIG was assessed on tumor-infiltrating lymphocytes from patients with various cancers, including non-small cell lung cancer (n = 63) and colorectal cancer (n = 26). The BsAb was engineered by fusing anti-PVRIG nanobodies to the N terminus of anti-TIGIT antibodies. Functional characterization of the BsAb was performed in vitro and in vivo, including assessments of T- and NK-cell activation and cytotoxicity. Pharmacokinetics and safety profiles were evaluated in cynomolgus monkeys. Statistical analyses were conducted using the Student t test. The results showed that the BsAb effectively blocked TIGIT and PVRIG from binding their respective ligands, CD155 and CD112, leading to significant increases in T-cell activation (2.8-fold; P < 0.05) and NK-cell cytotoxicity (1.8-fold; P < 0.05). In vivo, the BsAb demonstrated potent antitumor activity, both as a monotherapy and in combination with anti-PD-1 or anti-PD-L1, in humanized peripheral blood mononuclear cell-reconstituted and transgenic mouse models. Pharmacokinetic studies in cynomolgus monkeys revealed a favorable profile, with no dose-limiting toxicities observed after four repeated doses of 200 mg/kg. These findings provide compelling preclinical evidence for the therapeutic potential of targeting the TIGIT-PVRIG axis with a BsAb. This approach shows promise for enhancing antitumor immunity and warrants further investigation in clinical trials.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"664-677"},"PeriodicalIF":5.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029009","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":"TEAD-Independent Cell Growth of Hippo-Inactive Mesothelioma Cells: Unveiling Resistance to TEAD Inhibitor K-975 through MYC Signaling Activation.","authors":"Ken Akao, Tatsuhiro Sato, Emi Mishiro-Sato, Satomi Mukai, Farhana Ishrat Ghani, Lisa Kondo-Ida, Kazuyoshi Imaizumi, Yoshitaka Sekido","doi":"10.1158/1535-7163.MCT-24-0308","DOIUrl":"10.1158/1535-7163.MCT-24-0308","url":null,"abstract":"<p><p>Inactivation of tumor-suppressive Hippo signaling pathway is frequently observed in mesothelioma, which leads to the activation of yes-associated protein (YAP) and TAZ (also known as WW domain-containing transcription regulator 1; YAP/TAZ) transcriptional coactivators. YAP/TAZ form complexes with TEAD family members, DNA-binding proteins, to activate transcription, which promotes cancer cell growth and proliferation. Recently developed TEAD inhibitors exhibit antitumor activity by inhibiting the formation of the transcription complex through binding to TEAD; however, the antitumor activity of TEAD inhibitors against mesothelioma remains to be fully elucidated. Here, we show that the TEAD inhibitor K-975 acts as a pan-TEAD inhibitor and selectively inhibits the binding of TEAD-binding proteins, especially YAP/TAZ, in mesothelioma cells. In studies using a panel of mesothelioma cell lines, K-975 showed a significant growth inhibitory effect on Hippo-inactivated mesothelioma cells, but some of these cell lines exhibited primary resistance to K-975. Differential gene expression analysis revealed that cells resistant to K-975 exhibited activation of MYC signaling in the presence of K-975, and cells overexpressed with MYC showed strong drug resistance, in vitro and in vivo. Our study revealed the features of a subset of mesothelioma cells that proliferate in a TEAD-independent manner and provides important insights for the successful development of therapeutic strategies for mesothelioma with Hippo pathway inactivation.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"709-719"},"PeriodicalIF":5.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142837777","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":"Pathogenesis and Systemic Treatment of Hepatocellular Carcinoma: Current Status and Prospects.","authors":"Wanting Lei, Kexun Zhou, Ye Lei, Qiu Li, Hong Zhu","doi":"10.1158/1535-7163.MCT-24-0403","DOIUrl":"10.1158/1535-7163.MCT-24-0403","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) remains one of the major threats to human health worldwide. The emergence of systemic therapeutic options has greatly improved the prognosis of patients with HCC, particularly those with advanced stages of the disease. In this review, we discussed the pathogenesis of HCC, genetic alterations associated with the development of HCC, and alterations in the tumor immune microenvironment. Then, important indicators and emerging technologies related to the diagnosis of HCC are summarized. Also, we reviewed the major advances in treatments for HCC, offering insights into future prospects for next-generation managements.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"692-708"},"PeriodicalIF":5.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470223","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 discovery and characterization of HBS-101, a novel inhibitor of midkine, as a therapeutic agent for the treatment of triple negative breast cancer.","authors":"Megharani Mahajan, Alondra L Rodriguez Sanchez, Sridharan Jayamohan, Dileep K Vijayan, Jessica D Johnson, Huan Xie, Yang Wang, Dong Liang, John R Sanchez, Panneerdoss Subbarayalu, Manjeet K Rao, Ratna K Vadlamudi, Gangadhara R Sareddy, Hareesh B Nair, Suryavathi Viswanadhapalli","doi":"10.1158/1535-7163.MCT-25-0130","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0130","url":null,"abstract":"<p><p>Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor clinical outcome. There is a dire need for the development of new targeted therapies for TNBC. Midkine (MDK), a multifunctional cytokine/growth factor, functions as an oncoprotein and its expression is elevated in various cancers. The absence of small molecule inhibitors targeting MDK represents a significant knowledge gap for translation. In this study, we identified HBS-101 as a potent MDK-inhibitor with high specificity. Our modeling studies revealed that the interaction of HBS-101 with MDK is primarily driven by hydrophobic forces, and this interaction disrupted MDK's binding to its endogenous receptors. Microscale thermophoresis (MST), cellular thermal shift assay (CETSA) and biotin pulldown studies confirmed the direct interaction of HBS-101 with MDK. Therapeutically, HBS-101 treatment significantly reduced cell viability (IC50 0.3-2.8 µM), clonogenic survival, invasiveness, and increased apoptosis. The underlying mechanism of HBS-101 involves suppression of Akt/mTOR, STAT3, and NF-B pathways. Importantly, HBS-101 exhibits distinct pharmacologic advantages, including oral bioavailability, blood-brain-barrier penetration, and in vivo stability. Histologically, up to a dose of 10 mg/kg showed no observable organ toxicity and had no effect on the mice's body weight. Dose range studies identified 5 mg/kg as the minimal effective dose, achieving more than 50% tumor reduction. HBS-101 treatment led to a significant reduction in the growth of TNBC patient-derived xenograft tumors in vivo and markedly reduced TNBC brain-metastatic-tumor growth and prolonged mice survival. Collectively, our studies identified a first-in-class MDK inhibitor, HBS-101, that can be used to treat MDK-driven cancers.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033800","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":"Efficacy of ATR kinase inhibitor elimusertib monotherapy or combination in tumors with DNA damage response pathway and other genomic alterations.","authors":"Kaushik Varadarajan, Christian X Cruz Pico, Kurt W Evans, Maria Gabriela Raso, Yasmeen Qamar Rizvi, Xiaofeng Zheng, Dhruv Chachad, Timothy P DiPeri, Bailiang Wang, Stephen M Scott, Ming Zhao, Argun Akcakanat, Antje M Wengner, Timothy A Yap, Funda Meric-Bernstam","doi":"10.1158/1535-7163.MCT-24-0884","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0884","url":null,"abstract":"<p><p>The ataxia telangiectasia and RAD3-related (ATR) kinase functions with ataxia telangiectasia mutated (ATM) kinase as a modulator of DNA damage response (DDR). We assessed the antitumor effects of the ATR inhibitor elimusertib (BAY 1895344) in patient-derived xenograft (PDX) models with DDR alterations. Antitumor activity was assessed by change in tumor volume (TV) from baseline. Responses were categorized as follows: partial response (PR): >30% decrease in TV; >20% increase in TV: progressive disease (PD); and non-PR/PD: stable disease (SD). Event-free survival was defined as time for tumor doubling (EFS-2). Of 21 PDX models tested, 11 had significant prolongation of EFS-2 with elimusertib monotherapy. Four models had a PR and 4 had SD. PR/SD was observed in 2 of 5 models with ATM loss on IHC and in models with a variety of alterations in DDR genes, including BRCA1/2 and ATM. Elimusertib prolonged EFS-2 in three of 5 models with known PARP inhibitor resistance. Pharmacodynamic studies conducted in 4 PDX models showed an increase in DNA damage markers. PI3K/mTOR pathway signaling increased in 2 of 4 models. The combination of the PI3K inhibitor copanlisib with elimusertib enhanced EFS-2 compared to monotherapy in 3 of 11 models tested. The combination of elimusertib with the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib enhanced antitumor activity compared to single agents in PARP-resistant PDX models. Our study shows that ATR inhibition has antitumor activity, including in models with both intrinsic and acquired PARP inhibitor resistance. Further work is needed to better refine patient selection for ATR-based therapies.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024911","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}