Journal of Experimental & Clinical Cancer Research最新文献

{"title":"Targeting PRMT5 through PROTAC for the treatment of triple-negative breast cancer.","authors":"Yaxun Guo, Yuzhan Li, Zhongmei Zhou, Lei Hou, Wenjing Liu, Wenlong Ren, Dazhao Mi, Jian Sun, Xueqin Dai, Yingying Wu, Zhuo Cheng, Tingyue Wu, Qianmei Luo, Cong Tian, Fubing Li, Zhigang Yu, Yihua Chen, Ceshi Chen","doi":"10.1186/s13046-024-03237-y","DOIUrl":"10.1186/s13046-024-03237-y","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) is currently the most aggressive subtype of breast cancer, characterized by high heterogeneity and strong invasiveness, and currently lacks effective therapies. PRMT5, a type II protein arginine methyltransferase, is upregulated in numerous cancers, including TNBC, and plays a critical role, marked it as an attractive therapeutic target. PROTAC (Proteolysis Targeting Chimeras) is an innovative drug development technology that utilizes the ubiquitin-proteasome system (UPS) to degrade target proteins, which is characterized by higher activity, enhanced safety, lower resistance, and reduced toxicity, offering significant value for clinical translation.</p><p><strong>Methods: </strong>This study utilizes the PROTAC technology to develop potential degraders targeting PRMT5 in vitro and in vivo.</p><p><strong>Results: </strong>Through the design, synthesis and screening of a series of targeted compounds, we identified YZ-836P as an effective compound that exerted cytotoxic effects and reduced the protein levels of PRMT5 and its key downstream target protein KLF5 in TNBC after 48 h. Its efficacy was significantly superior to the PRMT5 PROTAC degraders that had been reported. YZ-836P induced G1 phase cell cycle arrest and significantly induced apoptosis in TNBC cells. Additionally, we demonstrated that YZ-836P promoted the ubiquitination and degradation of PRMT5 in a cereblon (CRBN)-dependent manner. Notably, YZ-836P exhibited pronounced efficacy in inhibiting the growth of TNBC patient-derived organoids and xenografts in nude mice.</p><p><strong>Conclusions: </strong>These findings position YZ-836P as a promising candidate for advancing treatment modalities for TNBC.</p><p><strong>Trial registration: </strong>Ethics Committee of Yunnan Cancer Hospital, KYCS2023-078. Registered 7 June 2023.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"314"},"PeriodicalIF":11.4,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11607928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in non-small cell lung cancer mechanomedicine: deciphering the signaling networks that govern tumor-TME interactions.","authors":"Antonios N Gargalionis, Kostas A Papavassiliou, Efthimia K Basdra, Athanasios G Papavassiliou","doi":"10.1186/s13046-024-03242-1","DOIUrl":"https://doi.org/10.1186/s13046-024-03242-1","url":null,"abstract":"<p><p>Cells from the tumor microenvironment (TME) interact with tumor cells in non-small cell lung cancer (NSCLC) to form a reciprocal crosstalk which influences tumor growth, proliferation, metastasis and multidrug response. This crosstalk is modulated by TME mechanical inputs, which elicit the processes of mechanosensing and mechanotransduction. Recent advances in unveiling these signaling networks establish the interdisciplinary field of mechanomedicine to exploit emerging diagnostic, predictive and therapeutic tools for more effective NSCLC treatments.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"316"},"PeriodicalIF":11.4,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11608457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis and the tumor microenvironment.","authors":"Kaisa Cui, Kang Wang, Zhaohui Huang","doi":"10.1186/s13046-024-03235-0","DOIUrl":"10.1186/s13046-024-03235-0","url":null,"abstract":"<p><p>Ferroptosis is a type of regulated cell death characterized by its non-apoptotic, iron-dependent and oxidative nature. Since its discovery in 2012, extensive research has demonstrated its pivotal roles in tumorigenesis, metastasis and cancer therapy. The tumor microenvironment (TME) is a complex ecosystem comprising cancer cells, non-cancer cells, extracellular matrix, metabolites and cytokines. Recent studies have underscored a new paradigm in which non-cancer cells in the TME, such as immune and stromal cells, also play significant roles in regulating tumor progression and therapeutic resistance typically through complicated crosstalk with cancer cells. Notably, this crosstalk in the TME were partially mediated through ferrotopsis-related mechanisms. This review provides a comprehensive and systematic summary of the current findings concerning the roles of ferroptosis in the TME and how ferroptosis-mediated TME reprogramming impacts cancer therapeutic resistance and progression. Additionally, this review outlines various ferroptosis-related therapeutic strategies aimed at targeting the TME.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"315"},"PeriodicalIF":11.4,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11607824/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AKT kinases as therapeutic targets.","authors":"Dalal Hassan, Craig W Menges, Joseph R Testa, Alfonso Bellacosa","doi":"10.1186/s13046-024-03207-4","DOIUrl":"10.1186/s13046-024-03207-4","url":null,"abstract":"<p><p>AKT, or protein kinase B, is a central node of the PI3K signaling pathway that is pivotal for a range of normal cellular physiologies that also underlie several pathological conditions, including inflammatory and autoimmune diseases, overgrowth syndromes, and neoplastic transformation. These pathologies, notably cancer, arise if either the activity of AKT or its positive or negative upstream or downstream regulators or effectors goes unchecked, superimposed on by its intersection with a slew of other pathways. Targeting the PI3K/AKT pathway is, therefore, a prudent countermeasure. AKT inhibitors have been tested in many clinical trials, primarily in combination with other drugs. While some have recently garnered attention for their favorable profile, concern over resistance and off-target effects have continued to hinder their widespread adoption in the clinic, mandating a discussion on alternative modes of targeting. In this review, we discuss isoform-centric targeting that may be more effective and less toxic than traditional pan-AKT inhibitors and its significance for disease prevention and treatment, including immunotherapy. We also touch on the emerging mutant- or allele-selective covalent allosteric AKT inhibitors (CAAIs), as well as indirect, novel AKT-targeting approaches, and end with a briefing on the ongoing quest for more reliable biomarkers predicting sensitivity and response to AKT inhibitors, and their current state of affairs.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"313"},"PeriodicalIF":11.4,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11606119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding the role of TNFR2 signaling in the tumor microenvironment of breast cancer.","authors":"Ali Mussa, Nor Hayati Ismail, Mahasin Hamid, Mohammad A I Al-Hatamleh, Anthony Bragoli, Khalid Hajissa, Noor Fatmawati Mokhtar, Rohimah Mohamud, Vuk Uskoković, Rosline Hassan","doi":"10.1186/s13046-024-03218-1","DOIUrl":"10.1186/s13046-024-03218-1","url":null,"abstract":"<p><p>Breast cancer (BC) is the most frequently diagnosed malignancy among women. It is characterized by a high level of heterogeneity that emerges from the interaction of several cellular and soluble components in the tumor microenvironment (TME), such as cytokines, tumor cells and tumor-associated immune cells. Tumor necrosis factor (TNF) receptor 2 (TNFR2) appears to play a significant role in microenvironmental regulation, tumor progression, immune evasion, drug resistance, and metastasis of many types of cancer, including BC. However, the significance of TNFR2 in BC biology is not fully understood. This review provides an overview of TNFR2 biology, detailing its activation and its interactions with important signaling pathways in the TME (e.g., NF-κB, MAPK, and PI3K/Akt pathways). We discuss potential therapeutic strategies targeting TNFR2, with the aim of enhancing the antitumor immune response to BC. This review provides insights into role of TNFR2 as a major immune checkpoint for the future treatment of patients with BC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"312"},"PeriodicalIF":11.4,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11603874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142752203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tailoring glioblastoma treatment based on longitudinal analysis of post-surgical tumor microenvironment.","authors":"Chiara Bastiancich, Emmanuel Snacel-Fazy, Samantha Fernandez, Stéphane Robert, Roberta Stacchini, Léa Plantureux, Sébastien Boissonneau, Benoit Testud, Benjamin Guillet, Franck Debarbieux, Hervé Luche, Dominique Figarella-Branger, Marie-Anne Estève, Emeline Tabouret, Aurélie Tchoghandjian","doi":"10.1186/s13046-024-03231-4","DOIUrl":"10.1186/s13046-024-03231-4","url":null,"abstract":"<p><p>Glioblastoma (GBM), an incurable primary brain tumor, typically requires surgical intervention followed by chemoradiation; however, recurrences remain fatal. Our previous work demonstrated that a nanomedicine hydrogel (GemC₁₂-LNC) delays recurrence when administered post-surgery. However, tumor debulking also triggers time-dependent immune reactions that promote recurrence at the resection cavity borders. We hypothesized that combining the hydrogel with an immunomodulatory drug could enhance therapeutic outcomes. A thorough characterization of the post-surgical microenvironment (SMe) is crucial to guide combinatorial approaches.In this study, we performed cellular resolution imaging, flow cytometry and spatial hyperplexed immunofluorescence imaging to characterize the SMe in a syngeneic mouse model of tumor resection. Owing to our dynamic approach, we observed transient opening of the blood-brain barrier (BBB) during the first week after surgery. BBB permeability post-surgery was also confirmed in GBM patients. In our murine model, we also observed changes in immune cell morphology and spatial location post-surgery over time in resected animals as well as the accumulation of reactive microglia and anti-inflammatory macrophages in recurrences compared to unresected tumors since the first steps of recurrence growth. Therefore we investigated whether starting a systemic treatment with the SMAC mimetic small molecule (GDC-0152) directly after surgery would be beneficial for enhancing microglial anti-tumoral activity and decreasing the number of anti-inflammatory macrophages around the GemC₁₂-LNC hydrogel-loaded tumor cavity. The immunomodulatory effects of this drug combination was firstly shown in patient-derived tumoroids. Its efficacy was confirmed in vivo by survival analysis and correlated with reversal of the immune profile as well as delayed tumor recurrence.This comprehensive study identified critical time frames and immune cellular targets within the SMe, aiding in the rational design of combination therapies to delay recurrence onset. Our findings suggest that post-surgical systemic injection of GDC-0152 in combination with GemC₁₂-LNC local treatment is a promising and innovative approach for managing GBM recurrence, with potential for future translation to human patient.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"311"},"PeriodicalIF":11.4,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11603899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142741289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective metabolic regulations by p53 mutant variants in pancreatic cancer.","authors":"Sabrina Caporali, Alessio Butera, Alessia Ruzza, Carlotta Zampieri, Marina Bantula', Sandra Scharsich, Anna-Katerina Ückert, Ivana Celardo, Ian U Kouzel, Luigi Leanza, Andreas Gruber, Joan Montero, Angelo D'Alessandro, Thomas Brunner, Marcel Leist, Ivano Amelio","doi":"10.1186/s13046-024-03232-3","DOIUrl":"10.1186/s13046-024-03232-3","url":null,"abstract":"<p><strong>Background: </strong>Approximately half of all human cancers harbour mutations in the p53 gene, leading to the generation of neomorphic p53 mutant proteins. These mutants can exert gain-of-function (GOF) effects, potentially promoting tumour progression. However, the clinical significance of p53 GOF mutations, as well as the selectivity of individual variants, remains controversial and unclear.</p><p><strong>Methods: </strong>To elucidate the metabolic regulations and molecular underpinnings associated with the specific p53^R270H and p53^R172H mutant variants (the mouse equivalents of human p53^R273H and p53^R175H, respectively), we employed a comprehensive approach. This included integrating global metabolomic analysis with epigenomic and transcriptomic profiling in mouse pancreatic cancer cells. Additionally, we assessed metabolic parameters such as oxygen consumption rate and conducted analyses of proliferation and cell-cell competition to validate the biological impact of metabolic changes on pancreatic ductal adenocarcinoma (PDAC) phenotype. Our findings were further corroborated through analysis of clinical datasets from human cancer cohorts.</p><p><strong>Results: </strong>Our investigation revealed that the p53^R270H variant, but not p53^R172H, sustains mitochondrial function and energy production while also influencing cellular antioxidant capacity. Conversely, p53^R172H, while not affecting mitochondrial metabolism, attenuates the activation of pro-tumorigenic metabolic pathways such as the urea cycle. Thus, the two variants selectively control different metabolic pathways in pancreatic cancer cells. Mechanistically, p53^R270H induces alterations in the expression of genes associated with oxidative stress and reduction in mitochondrial respiration. In contrast, p53^R172H specifically impacts the expression levels of enzymes involved in the urea metabolism. However, our analysis of cell proliferation and cell competition suggested that the expression of either p53^R270H or p53^R172H does not influence confer any selective advantage to this cellular model in vitro. Furthermore, assessment of mitochondrial priming indicated that the p53^R270H-driven mitochondrial effect does not alter cytochrome c release or the apoptotic propensity of pancreatic cancer cells.</p><p><strong>Conclusions: </strong>Our study elucidates the mutant-specific impact of p53^R270H and p53^R172H on metabolism of PDAC cancer cells, highlighting the need to shift from viewing p53 mutant variants as a homogeneous group of entities to a systematic assessment of each specific p53 mutant protein. Moreover, our finding underscores the importance of further exploring the significance of p53 mutant proteins using models that more accurately reflect tumor ecology.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"310"},"PeriodicalIF":11.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11590503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism of efficacy of trabectedin against myxoid liposarcoma entails detachment of the FUS-DDIT3 transcription factor from its DNA binding sites.","authors":"Ilaria Craparotta, Laura Mannarino, Riccardo Zadro, Sara Ballabio, Sergio Marchini, Giulio Pavesi, Marta Russo, Salvatore Lorenzo Renne, Marina Meroni, Marianna Ponzo, Ezia Bello, Roberta Sanfilippo, Paolo G Casali, Maurizio D'Incalci, Roberta Frapolli","doi":"10.1186/s13046-024-03228-z","DOIUrl":"10.1186/s13046-024-03228-z","url":null,"abstract":"<p><strong>Background: </strong>The marine drug trabectedin has shown unusual effectiveness in the treatment of myxoid liposarcoma (MLPS), a liposarcoma characterized by the expression of the FUS-DDIT3 chimera. Trabectedin elicits a significant transcriptional response in MLPS resulting in cellular depletion and reactivation of adipogenesis. However, the role of the chimeric protein in the mechanism of action of the drug is not entirely understood.</p><p><strong>Methods: </strong>FUS-DDIT3-specific binding sites were assessed through Chromatin Immunoprecipitation Sequencing (ChIP-Seq). Trabectedin-induced effects were studied on pre-established patient-derived xenograft models of MLPS, one sensitive to (ML017) and one resistant against (ML017ET) trabectedin at different time points (24 and 72 h, 15 days). Data were integrated with RNA-Seq from the same models.</p><p><strong>Results: </strong>Through ChIP-Seq, here we demonstrate that trabectedin inhibits the binding of FUS-DDIT3 to its target genes, restoring adipocyte differentiation in a patient-derived xenograft model of MLPS sensitive to trabectedin. In addition, complementary RNA-Seq data on the same model demonstrates a two-phase effect of trabectedin, characterized by an initial FUS-DDIT3-independent cytotoxicity, followed by a transcriptionally active pro-differentiation phase due to the long-lasting detachment of the chimera from the DNA. Interestingly, in a trabectedin-resistant MLPS model, the effect of trabectedin on FUS-DDIT3 rapidly decreased over time, and prolonged treatment was no longer able to induce any transcription or post-transcriptional modifications.</p><p><strong>Conclusions: </strong>These findings explain the unusual mechanism underlying trabectedin's effectiveness against MLPS by pinpointing the chimera's role in inducing the differentiation block responsible for MLPS pathogenesis. Additionally, the findings hint at a potential mechanism of resistance acquired in vivo.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"309"},"PeriodicalIF":11.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11590625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL14 suppresses the expression of YAP1 and the stemness of triple-negative breast cancer.","authors":"Xupeng Bai, Jiarui Liu, Shujie Zhou, Lingzhi Wu, Xiaojie Feng, Pumin Zhang","doi":"10.1186/s13046-024-03225-2","DOIUrl":"10.1186/s13046-024-03225-2","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) has pronounced stemness that is associated with relapse. N⁶-methyladenosine (m⁶A) plays a crucial role in shaping cellular behavior by modulating transcript expression. However, the role of m⁶A in TNBC stemness, as well as the mechanisms governing its abundance, has yet to be elucidated.</p><p><strong>Methods: </strong>We analyzed proteomic and transcriptomic data derived from breast cancer cohorts, with an emphasis on m⁶A regulators. To unravel the role of m⁶A in TNBC, we employed RNA sequencing, methylated RNA immunoprecipitation sequencing, RNA immunoprecipitation, chromatin immunoprecipitation, and luciferase reporter assays with mesenchymal stem-like (MSL) TNBC models. The clinical relevance was validated using human tissue microarrays and publicly accessible databases.</p><p><strong>Results: </strong>Our findings indicate that the global level of m⁶A modification in MSL TNBC is downregulated primarily due to the loss of methyltransferase-like 14 (METTL14). The diminished m⁶A modification is crucial for the maintenance of TNBC stemness, as it increases the expression of yes-associated protein 1 (YAP1) by blocking YTH domain-containing family protein 2 (YTHDF2)-mediated transcript decay, thereby promoting the activation of Hippo-independent YAP1 signaling. YAP1 is essential for sustaining the stemness regulated by METTL14. Furthermore, we demonstrated that the loss of METTL14 expression results from lysine-specific demethylase 1 (LSD1)-mediated removal of histone H3 lysine 4 methylation at the promoter region, which is critical for LSD1-driven stemness in TNBC.</p><p><strong>Conclusion: </strong>These findings present an epi-transcriptional mechanism that maintains Hippo-independent YAP1 signaling and plays a role in preserving the undifferentiated state of TNBC, which indicates the potential for targeting the LSD1-METTL14 axis to address TNBC stemness.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"307"},"PeriodicalIF":11.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual inhibition of HERs and PD-1 counteract resistance in KRAS^G12C-mutant head and neck cancer.","authors":"Ofra Novoplansky, Sankar Jagadeeshan, Manu Prasad, Ksenia M Yegodayev, Divyasree Marripati, Raghda Abu Shareb, Yariv Greenshpan, Sooraj Mathukkada, Talal Ben-Lulu, Baisali Bhattacharya, Angel Porgador, Dexin Kong, Johannes Brägelmann, J Silvio Gutkind, Moshe Elkabets","doi":"10.1186/s13046-024-03227-0","DOIUrl":"10.1186/s13046-024-03227-0","url":null,"abstract":"<p><strong>Background: </strong>Basket clinical trials targeting the KRAS^G12C-mutation in solid tumors have shown initial promise, including in orphan KRAS^G12C head and neck cancer (HNC). However, development of resistance to KRAS^G12C-mutant-specific inhibitors (KRAS^G12Ci) remains a major obstacle. Here, we investigated the intrinsic (tumor-cell autonomus) and tumor-microenvironment (TME) mechanisms of resistance to the KRAS^G12Ci-MRTX849 and AMG510 in a unique syngenic murine KRAS^G12C-mutated HNC cell line.</p><p><strong>Methods: </strong>Western-blotting was used for protein abundance and activation, overexpression, and ligand activation studies to verify the intrinsic mechanism of resistance to KRAS^G12Ci in KRAS^G12C-mutated HNC cell line, 4NQO-L. In vitro KRAS^G12C-acquired-resistant cells were developed from 4NQO-L (4NQO-L-AcR). MRTX849/lapatinib combination efficacy, and CD8⁺ T-cells depletion, were assessed in C57BL/6 J mice and supplementation of anti-PD-1 (αPD-1) to MRTX849/lapatinib was also performed in 4NQO-L- KRAS^G12Ci-senisitve and 4NQO-L-AcR tumors. Immunohistochemistry (IHC) and Immunoflourescence (IF) analyses were performed to profile the TME and programmed death-ligand 1 (PD-L1) expression in tumors.</p><p><strong>Results: </strong>Activation and upregulation of EGFR and HER2/3 (pan-HERs) are the intrinsic mechanism of resistance to KRAS^G12Ci in 4NQO-L cells, and blocking pan-HERs signaling with lapatinib enhanced MRTX849 efficacy in vitro by inhibiting the MAPK and AKT/mTOR pathways. 4NQO-L-AcR upregulated the expression of pan-HERs, and lapatinib treatment re-sensitized 4NQO-L-AcR to MRTX849. In mice, MRTX849 showed a slight anti-tumor effect, but in combination with lapatinib a significant tumor growth delay was observed, but all tumors progressed over time. Histopathology analysis of the TME revealed infiltration of CD8⁺ T-cells after treatment combination, and these CD8⁺ T-cells play a key role in MRTX849/lapatinib efficacy. MRTX849/lapatinib treatment upregulated PD-L1 overexpression in both stromal and tumor cells, which presumably suppressed CD8⁺ T-cells and enabled immune escape and tumor progression. Supplementation of αPD-1 prolonged the progression-free survival of 4NQO-L-bearing mice treated with MRTX849/lapatinib. MRTX849/lapatinib treatment delayed tumor growth of 4NQO-L-AcR in mice; however, the percentages of CD8⁺ T-cells in 4NQO-L-AcR were low, and supplementation of MRTX849/lapatinib with αPD-1 did not improve the outcome.</p><p><strong>Conclusions: </strong>Our study highlights the critical need for blocking both intrinsic and extrinsic mechanisms of resistance for the prolonged response and shows that such treatment is ineffective in KRAS^G12Ci-AcR tumors.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"308"},"PeriodicalIF":11.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}