Molecular Cancer Therapeutics最新文献

{"title":"Looking Beyond Checkpoint Inhibitor Monotherapy: Uncovering New Frontiers for Pancreatic Cancer Immunotherapy.","authors":"Eileena F Giurini, Oliver Ralph, Sam G Pappas, Kajal H Gupta","doi":"10.1158/1535-7163.MCT-24-0311","DOIUrl":"10.1158/1535-7163.MCT-24-0311","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) stands out as one of the most aggressive and challenging tumors, characterized by a bleak prognosis with a mere 11% survival rate over 5 years in the United States. Its formidable nature is primarily attributed to its highly aggressive behavior and poor response to existing therapies. PDAC, being notably resistant to immune interventions, presents a significant obstacle in treatment strategies. While immune checkpoint inhibitor therapies have revolutionized outcomes for various cancers, their efficacy in PDAC remains exceedingly low, benefiting less than 1% of patients. The consistent failure of these therapies in PDAC has prompted intensive investigation, particularly at the preclinical level, to unravel the intricate mechanisms of resistance inherent in this cancer type. This pursuit aims to pave the way for the development of novel immunotherapeutic strategies tailored to the distinct characteristics of PDAC. This review endeavors to provide a comprehensive exploration of these emerging immunotherapy approaches in PDAC, with a specific emphasis on elucidating their underlying immunological mechanisms. Additionally, it sheds light on the recently identified factors driving resistance to immunotherapy and evasion of the immune system in PDAC, offering insights beyond the conventional drivers that have been extensively studied.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"18-32"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291497","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":"PET Imaging Using 89Zr-Labeled StarPEG Nanocarriers Reveals Heterogeneous Enhanced Permeability and Retention in Prostate Cancer.","authors":"Niranjan Meher, Anil P Bidkar, Anju Wadhwa, Kondapa Naidu Bobba, Suchi Dhrona, Chandrashekhar Dasari, Changhua Mu, Cyril O Y Fong, Juan A Cámara, Umama Ali, Megha Basak, David Bulkley, Veronica Steri, Shaun D Fontaine, Jun Zhu, Adam Oskowitz, Rahul R Aggarwal, Renuka Sriram, Jonathan Chou, David M Wilson, Youngho Seo, Daniel V Santi, Gary W Ashley, Henry F VanBrocklin, Robert R Flavell","doi":"10.1158/1535-7163.MCT-24-0024","DOIUrl":"10.1158/1535-7163.MCT-24-0024","url":null,"abstract":"<p><p>The enhanced permeability and retention (EPR) effect controls passive nanodrug uptake in tumors and may provide a high tumor payload with prolonged retention for cancer treatment. However, EPR-mediated tumor uptake and distribution vary by cancer phenotype. Thus, we hypothesized that a companion PET imaging surrogate may benefit EPR-mediated therapeutic drug delivery. We developed two 89Zr-radiolabeled nanocarriers based on 4-armed starPEG40kDa with or without talazoparib (TLZ), a potent PARP inhibitor, as surrogates for the PEG-TLZ4 therapeutic scaffold. For PET imaging, PEG-DFB4 and PEG-DFB1-TLZ3 were radiolabeled with 89Zr by replacing one or all four copis of TLZ on PEG-TLZ4 with deferoxamine B (DFB). The radiolabeled nanodrugs [89Zr]PEG-DFB4 and [89Zr]PEG-DFB1-TLZ3 were tested in vivo in prostate cancer subcutaneous (s.c.) xenografts (22Rv1, LTL-545, and LTL-610) and 22Rv1 metastatic models. Their EPR-mediated tumoral uptake and penetration was compared with CT26, a known EPR-high cell line. MicroPET/CT images, organ biodistribution, and calculated kinetic parameters showed high uptake in CT26 and LTL-545 and moderate to low uptake in LTL-610 and 22Rv1. MicroPET/CT and high-resolution autoradiographic images showed nanocarrier penetration into highly permeable CT26, but heterogeneous peripheral accumulation was observed in LTL-545, LTL-610, and 22Rv1 s.c. xenografts and metastatic tumors. CD31 staining of tumor sections showed homogenous vascular development in CT26 tumors and heterogeneity in other xenografts. Both [89Zr]PEG-DFB4 and [89Zr]PEG-DFB1-TLZ3 showed similar accumulation and distribution in s.c. and metastatic tumor models. Both nanocarriers can measure tumor model passive uptake heterogeneity. Although heterogeneous, prostate cancer xenografts had low EPR. These starPEG nanocarriers could be used as PET imaging surrogates to predict drug delivery and efficacy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"141-151"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350348","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":"Tumor-Specific Antigen Delivery for T-cell Therapy via a pH-Sensitive Peptide Conjugate.","authors":"Annali M Yurkevicz, Yanfeng Liu, Samuel G Katz, Peter M Glazer","doi":"10.1158/1535-7163.MCT-23-0809","DOIUrl":"10.1158/1535-7163.MCT-23-0809","url":null,"abstract":"<p><p>Identifying an optimal antigen for targeted cancer therapy is challenging as the antigen landscape on cancerous tissues mimics that of healthy tissues, with few unique tumor-specific antigens identified in individual patients. pH low insertion peptide (pHLIP) acts as a unique delivery platform that can specifically target the acidic microenvironment of tumors, sparing healthy tissue in the process. We developed a pHLIP-peptide conjugate to deliver the SIINFEKL peptide, an immunogenic fragment of ovalbumin (OVA), to tumor cells in vivo. When processed intracellularly, SIINFEKL is presented for immune recognition through the major histocompatibility complex (MHC) class I pathway. We observed selective delivery of pHLIP-SIINFEKL both in vitro and in vivo using fluorescently labeled constructs. In vitro, treatment of melanoma tumor cells with pHLIP-SIINFEKL resulted in recognition by SIINFEKL-specific T cells (OT1), leading to T-cell activation and effector function. Mechanistically, we show that this recognition by OT1 T cells was abrogated by siRNA/shRNA knockdown of multiple components within the MHC class I pathway in the target tumor cells, indicating that an intact antigen processing pathway in the cancer cells is necessary to mediate the effect of pHLIP-directed SIINFEKL delivery. In vivo, pHLIP-SIINFEKL treatment of tumor-bearing mice resulted in the recruitment of OT1 T cells and suppression of tumor growth in two syngeneic tumor models in immunocompetent mice, with no effect when mutating either the pHLIP or SIINFEKL components of the conjugate. These results suggest that pHLIP-mediated peptide delivery can be used to deliver novel artificial antigens that can be targeted by cell-based therapies.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"105-117"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391895","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":"A Novel Lipid Nanoparticle NBF-006 Encapsulating Glutathione S-Transferase P siRNA for the Treatment of KRAS-Driven Non-small Cell Lung Cancer.","authors":"Cima Cina, Bharat Majeti, Zhihong O'Brien, Li Wang, Jean Pierre Clamme, Roger Adami, Kwok Yin Tsang, Jens Harborth, Wenbin Ying, Sonya Zabludoff","doi":"10.1158/1535-7163.MCT-23-0915","DOIUrl":"10.1158/1535-7163.MCT-23-0915","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers, and KRAS mutations occur in 25% to 30% of NSCLC. Our approach to developing a therapeutic with the potential to target KRAS-mutant NSCLC was to identify a new target involved in modulating signaling proteins in the RAS pathway. Glutathione S-transferase P (GSTP), known as a phase II detoxification enzyme, has more recently been identified as a modulator of MAPK-related cell signaling pathways. Therefore, developing a GSTP siRNA may be an effective therapeutic approach to treat KRAS-mutant NSCLC. The lead drug product candidate (NBF-006) is a proprietary siRNA-based lipid nanoparticle comprising GSTP siRNA (NDT-05-1040). Here, studies using a panel of KRAS-mutant NSCLC cell lines demonstrated that NDT-05-1040 is a very potent and selective GSTP siRNA inhibitor. Our Western blot analysis showed that NDT-05-1040 effectively decreased the phosphorylation of MAPK and PI3K pathway components while upregulating apoptotic signaling cascade. Our in vivo studies revealed statistically significant higher distribution of NBF-006 to the lungs and tumor as compared with the liver. In the subcutaneous and orthotopic tumor models, NBF-006 led to a statistically significant and dose-dependent antitumor growth inhibition. Furthermore, quantitative image analysis of proliferating cell nuclear antigen and PARP staining showed that NBF-006 decreased proliferation and induced apoptosis, respectively, in tumors. Additionally, in a surgically implanted orthotopic lung tumor model, the survival rate of the NBF-006 treatment group was significantly prolonged (P < 0.005) as compared with the vehicle control group. Together, these preclinical studies supported advancement of NBF-006 into clinical studies.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"7-17"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470221","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":"Riluzole Enhancing Anti-PD-1 Efficacy by Activating cGAS/STING Signaling in Colorectal Cancer.","authors":"Beiyuan Liang, Misbah Khan, Hayden Storts, Evan H Zhang, Xinru Zheng, Xuanxuan Xing, Hazel Claybon, Jenna Wilson, Chunjie Li, Ning Jin, Richard Fishel, Wayne O Miles, Jing J Wang","doi":"10.1158/1535-7163.MCT-24-0289","DOIUrl":"10.1158/1535-7163.MCT-24-0289","url":null,"abstract":"<p><p>Colorectal cancer is the second leading cause of cancer mortality in the United States. Although immune checkpoint blockade therapies including anti-PD-1/PD-L1 have been successful in treating a subset of patients with colorectal cancer, the response rates remain low. We have found that riluzole, a well-tolerated FDA-approved oral medicine for treating amyotrophic lateral sclerosis, increased intratumoral CD8+ T cells and suppressed tumor growth of colon cancer cells in syngeneic immune-competent mice. Riluzole-mediated tumor suppression was dependent on the presence of CD8+ T cells. Riluzole activates the cytosolic DNA sensing cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway in colon cancer cells, resulting in increased expression of IFNβ and IFNβ-regulated genes including CXCL10. Inhibition of ataxia telangiectasia mutated (ATM), but not ATM-related, resulted in a synergistic increase in IFNβ expression, suggesting that riluzole induces ATM-mediated damage response that contributes to cGAS/STING activation. Depletion of cGAS or STING significantly attenuated riluzole-induced expression of IFNβ and CXCL10 as well as increase of intratumoral CD8+ T cells and suppression of tumor growth. These results indicate that riluzole-mediated tumor infiltration of CD8+ T cells and attenuation of tumor growth is dependent on tumor cell-intrinsic STING activation. To determine whether riluzole treatment primes the tumor microenvironment for immune checkpoint modulation, riluzole was combined with anti-PD-1 treatment. This combination showed greater efficacy than either single agent and strongly suppressed tumor growth in vivo. Taken together, our studies indicate that riluzole activates cGAS/STING-mediated innate immune responses, which might be exploited to sensitize colorectal tumors to anti-PD-1/PD-L1 therapies.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"131-140"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391893","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":"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":"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}