Molecular Cancer Therapeutics最新文献

{"title":"Editor's Note: Cis-dichlorodiammineplatinum Upregulates Angiotensin II Type 1 Receptors through Reactive Oxygen Species Generation and Enhances VEGF Production in Bladder Cancer.","authors":"Nobuyuki Tanaka, Akira Miyajima, Takeo Kosaka, Suguru Shirotake, Masanori Hasegawa, Eiji Kikuchi, Mototsugu Oya","doi":"10.1158/1535-7163.MCT-26-0612","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-26-0612","url":null,"abstract":"","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":"25 8","pages":"1410"},"PeriodicalIF":6.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148670078","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":"NN-01-195, a Novel Conjugate of HSP90 and AURKA Inhibitors, Effectively Targets Solid Tumors.","authors":"Theodore T Nguyen, Nitesh K Nandwana, Yellamelli V V Srikanth, Tetyana Bagnyukova, Oleksandra Chkhalo, Kathy Q Cai, Julia Lamperelli, Shabnam Pirestani, Manish Kumar Mehra, Barbara A Burtness, Hossein Borghaei, Ravikumar Akunuri, Joel Cassel, Lily Lu, Joseph M Salvino, Erica A Golemis","doi":"10.1158/1535-7163.MCT-25-0857","DOIUrl":"10.1158/1535-7163.MCT-25-0857","url":null,"abstract":"<p><p>Aurora kinase A (AURKA) regulates cell-cycle progression into and through mitosis. As overexpression of AURKA in cancer cells is common and associated with mitotic defects and aneuploidy, small-molecule inhibitors of AURKA have been developed as candidate therapies for cancer. However, these have typically low activity in clinical trials, with systemic toxicities limiting dose escalation. To concentrate an AURKA inhibitor in tumors, we exploited the fact that cancer cells in solid tumors selectively express high levels of the chaperone HSP90 to counteract intratumoral stresses, providing a potential targeting moiety. We developed NN-01-195 as a novel chimeric small molecule that combines an AURKA inhibitor related to TAS-119/VIC-1911 with an HSP90-binding moiety related to SNX2112 and evaluated its function. NN-01-195 tightly binds and inhibits both AURKA and HSP90 in biochemical assays. In cancer cells, NN-01-195 causes mitotic arrest and spindle abnormalities and a profile of signaling changes that closely resembles that of an AURKA inhibitor. ADME assessment indicates moderate metabolism in liver microsomes (T1/2 = 46.7 minutes) and sustained plasma exposure following single intraperitoneal injection. Maximum tolerated repeated dose testing over 5 days indicates no weight loss or toxicity at 80 mg/kg. Importantly, NN-01-195 accumulates in xenografted tumors at higher levels and for longer duration than does an AURKA inhibitor. Furthermore, in combination with an inhibitor of the G2/M checkpoint protein WEE1, NN-01-195 is more potent than VIC-1911 in limiting growth of xenograft tumors. These data support the exploration of NN-01-195 and improved analogs as promising new candidates for therapeutic evaluation.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1231-1245"},"PeriodicalIF":6.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12977774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041327","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":"Anti-tumor activity of orally available cyclic peptide LUNA18 through direct pan-RAS inhibition across diverse RAS genetic alterations.","authors":"Hitoshi Sase, Saki Michisaka, Yukako Tachibana, Masami Hasegawa, Toshihiko Fujii, Kana Takei, Tomoko Kanei, Naoki Murao, Ryuichi Komatsu, Kentaro Asanuma, Shino Kuramoto, Norihito Shibahara, Atsushi Ohta, Mikimasa Tanada, Takuya Shiraishi, Hitoshi Iikura, Takehisa Kitazawa, Hiroshi Tanaka","doi":"10.1158/1535-7163.MCT-26-0262","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-26-0262","url":null,"abstract":"<p><p>Although recent extensive efforts led to the landmark discovery of clinically effective KRASG12C inhibitors (KRASG12C-i), targeting RAS genetic alterations beyond the G12C mutant remains challenging. Here we report on LUNA18 (paluratide), an orally available cyclic peptide that acts as a first-in-class pan-RAS GDP inhibitor, exhibiting potent inhibitory activity against a wide variety of RAS mutations. LUNA18 demonstrated anti-tumor effects against cancer cells with various RAS alterations, including G12 and G13 mutations as well as KRAS amplification. Moreover, LUNA18 showed synergistic anti-tumor effects when combined with agents targeting receptor tyrosine kinase (RTK) and the mitogen-activated protein kinase (MAPK) pathway. Notably, under long-term treatment and growth factor stimulation, LUNA18 induced more potent and sustained signal inhibition than KRASG12C-i. LUNA18 can sustain MAPK pathway suppression via RAS wild-type (RAS WT) inactivation, which produces this enhanced inhibitory effect in KRAS-mutant cancers where RAS WT acts as a critical regulator of MAPK signaling. In xenograft models where the efficacy of KRASG12C-i was limited, combination with LUNA18 achieved more durable anti-tumor effects compared with the monotherapies. These findings suggest that LUNA18 could be a promising new therapeutic option for RAS-driven cancers.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620487","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":"AZ'4331 is a novel pan-TEAD auto-palmitoylation inhibitor for the treatment of Hippo pathway-altered cancers.","authors":"Danielle J Sanchez, Jacob A Gordon, Ryan Richards, Erica Banks, Michelle DuPont, Jolanta Dubauskaite, Nicolas Floc'h, Eric Gosselin, Nin Guan, Niresh Hariparsad, Geoffrey A Holdgate, Clare Hoover, Alex Koers, Matthew J Martin, Scott Mlynarski, Uthpala Seneviratne, Abhishek Srivastava, Nancy Su, Jan M Suski, Neil T Umbreit, Man Xu, Corinne Reimer, Sabina Cosulich, James E Brownell","doi":"10.1158/1535-7163.MCT-25-1267","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-1267","url":null,"abstract":"<p><p>TEAD proteins are the transcriptional effectors of the Hippo signaling pathway that bind coactivators YAP/TAZ to activate gene expression programs involved in cell survival, proliferation, and drug resistance. TEAD-dependent transcription is elevated in many tumor types through a variety of mechanisms including loss-of-function mutations in Hippo pathway tumor suppressors, and as an adaptive resistance mechanism in response to EGFR TKI and KRAS inhibition. Therefore, targeting the YAP/TAZ-TEAD signaling axis has the potential to provide clinical benefit either as a monotherapy or combination strategy across diverse indications. Here, we characterize the activity of AZ'4331, a TEAD palmitoylation inhibitor which displays anti-tumor efficacy in multiple pre-clinical models of Hippo pathway-dysregulated cancers. Metabolic labeling studies show that TEAD proteins rapidly cycle between apo- and palmitoylated states, and that AZ'4331 inhibits the palmitoylation of TEAD1-4 paralogs. Functionally, AZ'4331 reduces YAP-TEAD binding and TEAD-dependent transcription, leading to reduced cell cycle progression and proliferation in Hippo pathway-altered NCI-H226 cells in vitro. AZ'4331 elicits robust monotherapy activity across mesothelioma and head and neck squamous cell carcinoma xenografts, and significantly enhances the efficacy of osimertinib in EGFR-mutant non-small cell lung cancer in vitro. However, this combination benefit only translates in vivo when osimertinib is administered at doses below clinically relevant levels, suggesting that TEAD inhibition enhances the efficacy of osimertinib in settings where EGFR signaling is incompletely suppressed. Collectively, these findings highlight the promise of TEAD inhibition as a therapeutic strategy for the treatment of Hippo pathway-driven cancers.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620479","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":"PF-08046876, a differentiated integrin beta-6 antibody-drug conjugate delivering a potent camptothecin payload optimized for bystander effect and reduced drug efflux.","authors":"Rebecca C Mazahreh, Chuan Bian Lim, Nicolas H Garcia, Devra J Olson, Ryan Lyski, Gina M LoMastro, Andrea Musa, Guadalupe Gutierrez, Samantha M Sarrett, R Greg Stacey, Li-Ya Huang, Kelly Hensley, Lori Westendorf, Sohinee Bhattacharyya, Narayana Yeddula, Vivian H Trang","doi":"10.1158/1535-7163.MCT-25-1509","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-1509","url":null,"abstract":"<p><p>Integrins represent a large family of cell surface receptors that exist as heterodimers with essential roles in key biological processes such as cellular adhesion, motility, and cytokinesis. Among them, integrin beta-6 (IB6), which exclusively dimerizes with integrin alpha-v, has emerged as a clinically relevant target due to its restricted expression in normal adult epithelial tissues and elevated levels in solid tumors. High expression of IB6 is correlated with poor prognosis across multiple solid tumor types. PF-08046876 is an investigational antibody-drug conjugate (ADC) consisting of the anti-IB6 monoclonal antibody conjugated to a camptothecin-class topoisomerase I (TOP1) inhibitor, AMDCPT, using a traceless enzyme-cleavable glucuronide linker. The AMDCPT payload has been optimized for differentiation from other TOP1 inhibitors with improved potency, enhanced bystander activity, and reduced susceptibility to multidrug resistance (MDR) efflux mechanisms. PF-08046876 leverages the same antibody backbone from sigvotatug vedotin (SV) and binds IB6 without cross-reactivity to other alpha-v integrin complexes. In preclinical studies, PF-08046876 has demonstrated significant antitumor activity both in vitro and in vivo across multiple tumor models with IB6 expression, including non-small cell lung (NSCLC), head and neck squamous cell (HNSCC), urothelial (UC), pancreatic (PDAC), and esophageal (ESCA) carcinomas. These findings support further clinical development of PF-08046876 as a promising therapeutic candidate for the treatment of IB6-expressing solid tumors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148605314","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":"Kinase Plasticity with Vandetanib Treatment Enhances Sensitivity to Tamoxifen in Estrogen Receptor Positive Breast Cancer.","authors":"Austin A Whitman, Rasha T Kakati, Santiago Haase, Christine Hnc Thai, Surya K Tripathi, Attila T Szenasi, Elizabeth C Brunk, Denis O Okumu, Michael P East, Sarahi G Molina, Adriana S Beltran, Jesse R Raab, Lisa A Carey, Charles M Perou, Gary L Johnson, Philip M Spanheimer","doi":"10.1158/1535-7163.MCT-26-0063","DOIUrl":"10.1158/1535-7163.MCT-26-0063","url":null,"abstract":"<p><p>Resistance to endocrine therapy (ET) is common in estrogen receptor-positive (ER+) breast cancer. Multiple studies have demonstrated that upregulation of MAPK signaling pathways contributes to ET resistance. Herein we show that vandetanib treatment suppresses MAPK signaling and enhances sensitivity to ET across ET-sensitive and ET-resistant ER+ cell lines and patient derived organoids. Vandetanib treatment reprograms transcription toward a less proliferative, more estrogen responsive, Luminal-A like state by enriching ERα chromatin binding at canonical estrogen response elements. Multiplexed kinase inhibitor beads-mass spectrometry (MIB/MS) revealed kinase network reprogramming, including upregulation of PI3K and HER2 activity, as shared adaptive resistance mechanisms to vandetanib treatment. Co-treatment with the HER2 inhibitor lapatinib, further enhanced sensitivity to vandetanib. Using an operating room-to-laboratory short-term ex-vivo assay coupled to single-cell RNA sequencing, we demonstrate conserved gene expression changes in primary tumor cells, including increased HER2 activity signatures, following vandetanib treatment. Vandetanib sensitivity signatures were generated from cell line and primary human tumor cells which correlate with vandetanib sensitivity in ER+ patient-derived organoid and xenograft models. Future studies should evaluate if signatures predict responses in patients with ER+ breast tumors, and determine the role of co-targeting HER2 signaling with vandetanib therapy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13491284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148605320","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":"New Therapeutic Cancer Vaccine with Lenalidomide Induces Potent T Cell Immunity and Inhibits HPV E6/E7-Expressing Tumor Growth in Mice.","authors":"Yohannes Gemechu, Sonia Mukherjee, Jeffrey A Gelfand, Timothy A Brauns, Ann E Sluder, Pierre R Leblanc, Yuki Agarwala, James Adeosun, Abigail Colley, Daiki Sugita, Jacob J Smith, George Steinfels, Paul Korner, Ishan Capila, Patrick M Reeves, Mark C Poznansky","doi":"10.1158/1535-7163.MCT-25-1488","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-1488","url":null,"abstract":"<p><p>Current prophylactic human papillomavirus (HPV) vaccines prevent infection but have limited therapeutic benefit in established HPV-driven malignancies. To address this unmet need, we developed VTX-067, a modular self-assembling therapeutic cancer vaccine consisting of a recombinant Mycobacterium tuberculosis heat shock protein 70-avidin fusion (MAV) noncovalently bound to biotinylated HPV E6/E7 MHC class I- and II-restricted peptide concatemers. MAV is produced in CHO cells with minimal endotoxin. Assembled VTX-067 is designed to elicit both CD4⁺ and CD8⁺ T-cell responses against HPV-associated tumors. In multiple tumor models expressing HPV E6/E7, intradermal vaccination with VTX-067 induced potent and dose-dependent HPV E6/E7-specific CD8⁺ and CD4⁺ T-cell responses without evidence of local reactogenicity. Therapeutic vaccination significantly delayed subcutaneous tumor progression, extended survival, and provided durable protection against tumor rechallenge. VTX-067 treatment increased intratumoral CD8⁺ T-cell infiltration, elevated the CD8:Treg ratio, and upregulated a Th1/cytotoxic transcriptional program including Ifnγ, Tbx21, Stat1, and Gzmb. Depletion of CD8⁺ T cells eliminated vaccine efficacy, while adoptive transfer of VTX-067-primed CD8⁺ T cells conferred tumor protection in recipient mice. In a cervicovaginal orthotopic model, both intradermal and intramucosal administration generated systemic E6/E7-specific effector responses and sustained control of mucosal tumors. Notably, combining a suboptimal VTX-067 dose with the immunomodulatory agent lenalidomide further enhanced tumor control and survival, demonstrating a potential dose-sparing strategy. These findings establish VTX-067 as a safe, highly immunogenic therapeutic vaccine with CD8⁺ T-cell-dependent antitumor activity, and support its clinical development alone or in combination with immune-modulating agents for HPV-associated cancers.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148584669","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":"Development of tandem canine CAR T cells to enable comparative studies of aggressive B-cell lymphoma.","authors":"Brandon Peng, Lang Jiang, Jennifer A Lenz, Luiza Cesar Conti, Antonia Rotolo, Nicola J Mason, Matthew J Atherton","doi":"10.1158/1535-7163.MCT-26-0365","DOIUrl":"10.1158/1535-7163.MCT-26-0365","url":null,"abstract":"<p><p>Anti-CD19 chimeric antigen receptor T (CAR T) cells have promising therapeutic potential for diffuse large B-cell lymphoma (DLBCL), yet many treated patients relapse due to progressive disease driven by CD19-negative clones. Tandem CAR (TCAR) designs co-targeting CD19 and CD20 may overcome this problem. However, murine and primate models do not fully recapitulate human disease and clinical responses to CAR T therapy, limiting preclinical optimization. Moreover, clinical trials are lengthy and costly, further delaying the evaluation of new strategies. By contrast, canine DLBCL closely resembles the human disease, and CAR T trials in canines are feasible, with clinical sequelae that mirror those observed in human CAR T therapy. We previously reported CD20 loss in canine DLBCL patients treated with CD20-specific CAR T cells, consistent with mechanisms of antigen escape in humans. We therefore hypothesized that canine DLBCL could be leveraged to accelerate the translation of more effective TCAR-based strategies, benefiting both canine and human patients. To test this, we first assessed the expression of CD19 and CD20 in canine lymphoma patient samples. We then developed canine TCARs directed against CD19 and CD20 and evaluated their efficacy and specificity against canine DLBCL cells. We show that canine B-cell lymphoma co-expresses CD19 and CD20 with heterogeneous expression patterns similar to those observed in humans, and that TCAR-engineered canine T cells effectively and specifically eliminate cells expressing CD19 and/or CD20. Our TCAR platform holds promise to improve outcomes in canine DLBCL and to further optimize next-generation CAR-based strategies before entering human trials.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13456398/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549649","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":"PMS1 loss defines distinct mismatch repair complex deficiencies across dog and human cancers.","authors":"Deborah Wilsker, Asma Begum, Alan Brooks, Ralph E Parchment, James H Doroshow","doi":"10.1158/1535-7163.MCT-26-0249","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-26-0249","url":null,"abstract":"<p><p>Tumors in pet dogs provide a valuable comparative model for evaluating immune checkpoint inhibitor (ICI) therapies in humans. Whether mismatch repair deficiency (MMRd) predicts response to ICI in dogs, as it does in humans, remains unknown. To enable biomarker-driven clinical trials, development of a validated canine mismatch repair (MMR) assay is required. Mass spectrometry identified PMS1 as the binding partner of MLH1 in dogs, rather than PMS2. A novel monoclonal antibody was developed to detect PMS1 in both canine and human tissues by immunohistochemistry (IHC). A multiplex immunofluorescence assay was established to simultaneously detect MLH1, MSH2, MSH6, and PMS2 in parallel to PMS1. MMR protein expression profiles were characterized across 39 human colorectal cancers, 25 patient-derived xenografts (PDXs), and 43 canine tumor samples. PMS1 is frequently lost in conjunction with MLH1 and PMS2 in human colorectal and endometrial tumors. In canine cancers, lymphomas and mast cell tumors demonstrated a high incidence of MMRd typified by the loss of two or more markers, frequently including MLH1/PMS1. Loss of PMS1 alone occurred in three of 19 canine soft tissue sarcomas. A standardized definition of MMRd in dogs is essential to advance biomarker-driven ICI trials. The multiplex MMR assay described here enables detection of MMRd across species and tumor types. MMRd is a frequent event in common canine cancers, establishing dogs as a relevant model for evaluating ICI therapies. These MMR assays are now suitable for implementation in canine biomarker-guided clinical studies.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549638","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":"LIG1 Loss in TP53-mutant Triple Negative Breast Cancer Rewires DNA Repair and Confers Sensitivity to PARP-ATR Inhibitor Combinations.","authors":"Anh Minh Tran Huynh, Jonathan T Lei, Rachel Brough, Christina Sallas, Jun Xu, Jacob B Pilcher, Xuxu Gou, Junkai Wang, Lacey E Dobrolecki, Diana M Fandino, Mariah J Berner, Allison Greer, Fei Fei Song, Sarah Latka, Hugo Villanueva, Sumimasa Arimura, Sufeng Mao, Zhongqiu Guo, Sofía I Aramburu, Anran Chen, Thanh Nguyen, Carolina Gutierrez, Dolores H Lopez-Terrada, Bora Lim, Susan G Hilsenbeck, Michael T Lewis, George Miles, Jason C Mills, Gloria V Echeverria, Stephen J Pettitt, Simon N Powell, Susan M Rosenberg, Andrew N J Tutt, Christopher J Lord, Matthew J Ellis, Meenakshi Anurag","doi":"10.1158/1535-7163.MCT-26-0182","DOIUrl":"10.1158/1535-7163.MCT-26-0182","url":null,"abstract":"<p><p>Proteogenomic analyses have identified an association between LIG1 (DNA Ligase I) loss and chemotherapy resistance in a subset of triple negative breast cancer (TNBC) enriched for TP53 mutations. Here, we demonstrate that co-occurrence of TP53 mutations and LIG1 loss is associated with upregulated DDR activity, including homologous recombination, likely contributing to reduced platinum sensitivity. Unbiased genetic and monotherapy drug screens identified PARP inhibitors (PARPi) as a potential treatment for LIG1-depleted tumors; however, the increase in sensitivity was modest and lower than that observed in TNBC models with homologous recombination deficiency. Subsequently, a screen of PARP inhibition in combination with each of 120 clinically relevant DDR inhibitors revealed that PARPi sensitivity in LIG1-loss cells was significantly enhanced by the addition of an ATR inhibitor (ATRi). Olaparib and ceralasertib demonstrated synergistic cytotoxicity in LIG1-loss cell line models; the combination significantly reduced tumor volume in a LIG1-low PDX model compared to either monotherapy, and showed greater ex vivo cytotoxicity in a LIG1-low PDXO model versus a LIG1-high control. Hence, this study highlights LIG1 status as a stratification factor for ongoing and future clinical trials of DDR-targeted combinations in TNBCs.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13482947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456328","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}