Molecular Cancer Therapeutics最新文献

{"title":"Advances and Challenges in RAS Signaling Targeted Therapy in Leukemia.","authors":"Yu Chen, Zhenghao Yin, Kenneth D Westover, Zhiwei Zhou, Liping Shu","doi":"10.1158/1535-7163.MCT-24-0504","DOIUrl":"10.1158/1535-7163.MCT-24-0504","url":null,"abstract":"<p><p>RAS mutations are prevalent in leukemia, including mutations at G12, G13, T58, Q61, K117, and A146. These mutations are often crucial for tumor initiation, maintenance, and recurrence. Although much is known about RAS function in the last 40 years, a substantial knowledge gap remains in understanding the mutation-specific biological activities of RAS in cancer and the approaches needed to target specific RAS mutants effectively. The recent approval of KRASG12C inhibitors, adagrasib and sotorasib, has validated KRAS as a direct therapeutic target and demonstrated the feasibility of selectively targeting specific RAS mutants. Nevertheless, KRASG12C remains the only RAS mutant successfully targeted with FDA-approved inhibitors for cancer treatment in patients, limiting its applicability for other oncogenic RAS mutants, such as G12D, in leukemia. Despite these challenges, new approaches have generated optimism about targeting specific RAS mutations in an allele-dependent manner for cancer therapy, supported by compelling biochemical and structural evidence, which inspires further exploration of RAS allele-specific vulnerabilities. This review will discuss the recent advances and challenges in the development of therapies targeting RAS signaling, highlight emerging therapeutic strategies, and emphasize the importance of allele-specific approaches for leukemia treatment.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"33-46"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470222","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":"PARP7 Inhibitors and AHR Agonists Act Synergistically across a Wide Range of Cancer Models.","authors":"Huadong Chen, Xuxu Gou, Ying Mao, Patrick C O'Leary, Morgan E Diolaiti, Alan Ashworth","doi":"10.1158/1535-7163.MCT-24-0211","DOIUrl":"10.1158/1535-7163.MCT-24-0211","url":null,"abstract":"<p><p>Small-molecule inhibitors of the mono (ADP) ribosyl transferase PARP7 are being evaluated asmonotherapy for tumors overexpressing PARP7 and in combination with immune checkpoint blockade. We previously showed that sensitivity to the PARP7 inhibitor (PARP7i) RBN-2397 could be enhanced by cotreatment with agonists of the aryl hydrocarbon receptor (AHRa) in cell lines that show strong intrinsic sensitivity to RBN-2397. In this study, we demonstrated that a range of tumor cell lines that are relatively insensitive to PARP7i or AHRa as individual agents are unexpectedly profoundly sensitive to their combination. Our data show that this synergistic response is dependent on the AHR/AHR nuclear translocator and is associated with increased levels of nuclear AHR and increased transcription of AHR target genes. In some hormone receptor-positive cell lines, we find that combination treatment is associated with proteasomal turnover of the steroid hormone receptors, androgen receptor and estrogen receptor. Both wild-type and hormone-resistant mutant forms of these receptors are degraded upon treatment with AHRa and PARP7i in breast and prostate cancer models. These results suggest that combining PARP7i with AHRa may extend the utility of these drugs to a wider range of tumors, including those that are refractory to hormone therapy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"56-68"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308092","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":"A Small-Molecule BCL6 Inhibitor as an Anti-Proliferative Agent for Diffuse Large B-Cell Lymphoma.","authors":"Yajing Xing, Weikai Guo, Min Wu, Jiuqing Xie, Dongxia Huang, Pan Hu, Miaoran Zhou, Lin Zhang, Yadong Zhong, Mingyao Liu, Yihua Chen, Zhengfang Yi","doi":"10.1158/1535-7163.MCT-23-0830","DOIUrl":"10.1158/1535-7163.MCT-23-0830","url":null,"abstract":"<p><p>The B-cell lymphoma 6 (BCL6) transcription factor plays a key role in the establishment of germinal center (GC) formation. Diffuse large B-cell lymphoma (DLBCL) originates from the GC reaction due to dysregulation of BCL6. Disrupting BCL6 and its corepressors' interaction has become the foundation for rationally designing lymphoma therapies. However, BCL6 inhibitors with good activities in vitro and in vivo are rare, and there are no clinically approved BCL6 inhibitors. In this study, we discovered and developed a novel range of [1,2,4] triazolo[1,5-a] pyrimidine derivatives targeting BCL6/SMRT interaction. The lead compound WK692 directly bound BCL6BTB, disrupted BCL6BTB/SMRT interaction and activated the expression of BCL6 downstream genes inside cells, inhibited DLBCL growth and induced apoptosis in vitro, inhibited GC formation, decreased the proportion of follicular helper T cells, and impaired Ig affinity maturation. Further studies showed that WK692 inhibits DLBCL growth without toxic effects in vivo and synergizes with the EZH2 and PRMT5 inhibitors. Our results demonstrated that WK692 as a BCL6 inhibitor may be developed as a novel potential anticancer agent against DLBCL.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"81-92"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391892","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":"Ultra-High 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":"https://doi.org/10.1158/1535-7163.MCT-24-0536","url":null,"abstract":"<p><p>Ultra-high dose rate radiotherapy 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 ultra-high-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/s) and FLASH (at 141 Gy/s) radiotherapy 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 (DSB). 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 (iNOS). Tumor response to SDR (0.2 Gy/s) and FLASH (250 Gy/s) radiotherapy was evaluated in A549 carcinoma model, using tumor volume and Kaplan-Meier survival as endpoints. The results showed that helium FLASH radiotherapy significantly reduced acute brain tissue injury compared to SDR, evidenced by lower levels of DSB and preserved neurovascular endothelium. Additionally, FLASH radiotherapy reduced neuroinflammatory signals compared to SDR, as indicated by fewer CD68+ iNOS+ microglia/macrophages. FLASH radiotherapy achieved tumor control comparable to that of SDR radiotherapy. This study is the first to report the FLASH sparing effect of raster scanning helium ion radiotherapy in vivo, highlighting its potential for neuroprotection and effective tumor control.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"OBI-992, a Novel TROP2-Targeted Antibody-Drug Conjugate, Demonstrates Antitumor Activity in Multiple Cancer Models.","authors":"Wan-Fen Li, Ming-Feng Chiang, Hao-Cheng Weng, Jhih-Jie Yang, Hsin-Shan Wu, Szu-Yu Wu, Yu-Jung Chen, Chi-Huan Lu, Jyy-Shiuan Tu, Ren-Yu Hsu, Chi-Sheng Shia, Teng-Yi Huang, Ming-Tain Lai","doi":"10.1158/1535-7163.MCT-24-0588","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0588","url":null,"abstract":"<p><p>Trophoblast cell surface antigen 2 (TROP2) is highly expressed in multiple cancers relative to normal tissues, supporting its role as a target for cancer therapy. OBI-992 is an antibody-drug conjugate (ADC) derived from a novel TROP2-targeted antibody linked to the topoisomerase 1 (TOP1) inhibitor exatecan via an enzyme-cleavable hydrophilic linker, with a drug-antibody ratio of 4. This study evaluated and compared the antitumor activity of OBI-992 with that of benchmark TROP2-targeted ADCs datopotamab deruxtecan (Dato-DXd) and sacituzumab govitecan (SG) in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. OBI-992 treatment exhibited statistically significant antitumor activity versus controls at doses of 3 and 10 mg/kg in various CDX and PDX models, demonstrating comparable or better antitumor activity with benchmark ADCs. In a large-tumor model, longer survival times were observed in OBI-992-treated mice compared with Dato-DXd-treated mice. OBI-992 treatment induced marked bystander killing of TROP2-negative cells in the presence of nearby TROP2-positive cells in both in vitro and in vivo studies. In lung adenocarcinoma CDX models with overexpression of either P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) to mimic ATP-binding cassette transporter-mediated multidrug resistance, OBI-992 treatment maintained antitumor activity when Dato-DXd treatment became less effective. The combination of OBI-992 at suboptimal doses with either poly (ADP-ribose) polymerase (PARP) inhibitors or an immune check point inhibitor produced synergistic antitumor effects in mouse models. Taken together, these translational results support further development of OBI-992 as a cancer therapy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF13"},"PeriodicalIF":5.3,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951560","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":"Pan-KRAS inhibitors BI-2493 and BI-2865 display potent anti-tumor activity in tumors with KRAS wild-type allele amplification.","authors":"Antonio Tedeschi, Fiorella Schischlik, Francesca Rocchetti, Johannes Popow, Florian Ebner, Daniel Gerlach, Antonia Geyer, Valeria Santoro, Andrew S Boghossian, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Jesse Lipp, Matthias Samwer, Michael Gmachl, Norbert Kraut, Mark Pearson, Dorothea Rudolph","doi":"10.1158/1535-7163.MCT-24-0386","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0386","url":null,"abstract":"<p><p>KRASG12C selective inhibitors, such as sotorasib and adagrasib, have raised hopes of targeting other KRAS mutant alleles in cancer patients. We report that KRAS wild-type amplified tumor models are sensitive to treatment with the small molecule KRAS inhibitors BI-2493 and BI-2865. These pan-KRAS inhibitors directly target the \"OFF\" state of KRAS and result in potent anti-tumor activity in pre-clinical models of cancers driven by KRAS mutant proteins. Here, we used the high-throughput cellular viability PRISM assay to assess the anti-proliferative activity of BI-2493 in a 900+ cancer cell line panel, expanding on our previous work. KRAS wild-type amplified cancer cell lines, with a copy number >7, were identified as the most sensitive, across cell lines with any KRAS alterations, to our pan-KRAS inhibitors. Importantly, our data suggest that a KRAS \"OFF\" inhibitor is better suited to treat KRAS wild-type amplified tumors than a KRAS \"ON\" inhibitor. KRAS wild-type amplification is common in patients with gastroesophageal cancers where it has been shown to act as a unique cancer driver with little overlap to other actionable mutations. The pan-KRAS inhibitors BI-2493 and BI-2865 show potent anti-tumor activity in vitro and in vivo in KRAS wild-type amplified cell lines from this and other tumor types. In conclusion, this is the first study to demonstrate that direct pharmacological inhibition of KRAS shows anti-tumor activity in preclinical models of cancer with KRAS wild-type amplification, suggesting a novel therapeutic concept for patients with cancers bearing this KRAS alteration.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877408","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":"Blocking feedback immunosuppression of antigen presentation in brain tumor during oncolytic virotherapy with oHSV-mshPKR.","authors":"Nobushige Tsuboi, Kimberly A Rivera-Caraballo, Upasana Sahu, Rafal Pacholczyk, Eugene Douglass, Theodore S Johnson, Qin Wang, Ravindra Kolhe, Catherine C Hedrick, David H Munn, Bangxing Hong","doi":"10.1158/1535-7163.MCT-24-0629","DOIUrl":"10.1158/1535-7163.MCT-24-0629","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most frequent malignant brain tumor. We recently discovered that oncolytic herpes simplex virus engineered to disable tumor-intrinsic protein kinase R (PKR) signaling (oHSV-shPKR) could increase oHSV oncolysis and anti-tumor immune response. However, here we show that disabling tumor-intrinsic PKR signaling can also induce the activation of the indoleamine 2,3-dioxygenase (IDO) signaling pathway. Both GBM tumor progression and oHSV intratumoral therapy increased infiltration of IDO+CD11c+ dendritic cells into the tumor. The coculture of oHSV-infected human GBM neurospheres with monocytes-derived dendritic cells (MoDCs) dramatically increased IDO signaling activation in MoDCs through type-I interferon signaling. Addition of IDO inhibitor (indoximod) in the coculture significantly increased MoDCs activation and reduced the consumption of tryptophan. Combining indoximod and oHSV significantly inhibited tumor growth, and induced antigen specific CD8+ T cell activation. These results suggest that inhibition of the IDO pathway could significantly block feedback immunosuppression during oncolytic virotherapy of glioblastoma.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877405","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":"Combination of Bremachlorin PDT and immune checkpoint inhibitor anti-PD-1 shows response in murine immunological T-cell high and T-cell low PDAC models.","authors":"Roisin McMorrow, Henriette S de Bruijn, Stefania Farina, Ruben J L van Ardenne, Ivo Que, Pier G Mastroberardino, Dominic J Robinson, Laura Mezzanotte, Clemens W G M Löwik","doi":"10.1158/1535-7163.MCT-23-0733","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0733","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is one of the most challenging types of cancer with little or no response to immune checkpoint inhibitors (ICIs). Photodynamic therapy (PDT) has been shown to ablate tumors and induce an immune response. In our study, we investigated the effect of photodynamic therapy (PDT), using the photosensitizer Bremachlorin, in its ability to reduce tumor burden and to sensitize immunologically T-cell high and T-cell low murine PDAC tumors to the ICI that blocks programmed cell death-1 (PD-1) immune checkpoint. In addition, we monitored the effect on survival and investigated if there was a response in PDT-treated and non PDT-treated distant tumors. Our results showed that Bremachlorin PDT induces direct tumor killing which increased survival in both 'hot' T-cell high and 'cold' T-cell low PDAC tumors and that it can make the T-cell high tumors more sensitive to ICI blocking PD-1. We found that T-cell high tumor bearing mice had an overall greater response to therapy than T-cell low tumor bearing mice. One mouse with T-cell high tumors exhibited complete tumor regression in both the treated and non-treated distant tumor 90 days after treatment. These results indicate that combining immune checkpoint inhibitors (ICIs) with Bremachlorin PDT could be a promising therapeutic intervention for enhancing PDAC's response to therapy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864854","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":"First-in-human Study of ABY-029, a Novel Fluorescent Peptide that Targets Epidermal Growth Factor Receptor, 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":"https://doi.org/10.1158/1535-7163.MCT-24-0378","url":null,"abstract":"<p><p>ABY-029, an anti-epidermal growth factor receptor (EGFR) Affibody® molecule conjugated to IRDye 800CW, recently underwent first-in-human testing in soft-tissue sarcoma (STS). FDA Exploratory Investigational New Drug status was obtained for the Phase 0 clinical trial in which study objectives were to determine whether biological variance ratio (BVR) of 10 was achievable, fluorescence intensity correlated with EGFR expression, and doses were well tolerated. Patients (N=12) with STS were recruited based on positive EGFR immunohistochemical staining of diagnostic biopsies. ABY-029 was administered at micro- (30 nanomole, n=3), medium (90 nanomole, n=3), or high dose (171 nanomole, n=6), 1-3 hours prior to surgery. Following tumor resection, ex vivo tissue was imaged to determine mean fluorescence intensity (MFI), BVR, and other contrast measures. EGFR expression was correlated with immunohistochemistry. For micro-, medium, and high doses, mean BVR (SD) in cross-sectional slices were 4 (4), 10 (6), and 7 (8), respectively, for the whole tumor region and 6 (5), 13 (11), and 8 (6), respectively, for pathology-confirmed regions-of-interest. 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 MFI 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 high correlation to EGFR expression and contrast values that were encouraging for translation to clinical practice. Contrast was similar to those observed with antibody agents, but with substantially reduced imaging-to-resection time, and no drug-related adverse events.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-12-17","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":"Olaparib and Radiotherapy Induce Type I Interferon- and CD8+ T Cell-Dependent Sensitization to Immunotherapy in Pancreatic Cancer.","authors":"Victoria M Valvo, Qiang Zhang, Long Jiang, Erin A Holcomb, Ashley N Pearson, Anna G Edmunds, Hailey G Faulkner, Jadyn G James, Akshay Tate, Amanda K Huber, Zhuwen Wang, Yupei Guo, David Karnak, Leslie A Parsels, Joshua D Parsels, Yu L Lei, Alnawaz Rehemtulla, Heng Lin, Eileen S Carpenter, Daniel R Wahl, Vaibhav Sahai, Theodore S Lawrence, Michael D Green, Meredith A Morgan","doi":"10.1158/1535-7163.MCT-24-0210","DOIUrl":"10.1158/1535-7163.MCT-24-0210","url":null,"abstract":"<p><p>PARP inhibitors sensitize pancreatic ductal adenocarcinoma (PDAC) to radiation by inducing DNA damage and replication stress. These mechanisms also have the potential to enhance radiation-induced type I interferon (T1IFN)-mediated antitumoral immune responses. We hypothesized that the PARP inhibitor olaparib would also potentiate radiation-induced T1IFN to promote antitumor immune responses and sensitization of otherwise resistant PDAC to immunotherapy. To test this hypothesis, we assessed the effects of olaparib and radiation on T1IFN production and sensitivity to αPD-L1 immunotherapy, as well as on the tumor microenvironment by single-cell RNA sequencing. We found that olaparib enhanced T1IFN production after radiation and had superior therapeutic efficacy in immunocompetent models. Olaparib and radiation treatment sensitized PDAC tumors to αPD-L1, resulting in decreased tumor burden and a 33% complete response rate. Combination treatment provided durable immune responses as shown by tumor rejection upon tumor rechallenge of previously cured mice. Furthermore, single-cell RNA sequencing analysis revealed that combination treatment induced an immunogenic tumor microenvironment characterized by interferon (IFN) responses in both PDAC and myeloid cell populations, macrophage polarization, and increased CD8+ terminal effector T-cell frequency and activity, findings which were confirmed by IHC and flow cytometry. Furthermore, CD8+ T cells and T1IFN signaling were required for therapeutic efficacy as host depletion of CD8+ T cells or the T1IFN receptor diminished treatment responses. Overall, our results indicate that olaparib enhances radiation-induced T1IFN-mediated immune signaling and subsequently an adaptive immune response, thus sensitizing pancreatic cancer to αPD-L1 therapy, supporting an ongoing clinical trial of this therapy in patients with PDAC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF16"},"PeriodicalIF":5.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142837771","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}