Molecular Cancer Therapeutics最新文献

{"title":"Unveiling the Mechanism of Lurbinectedin's Action and Its Potential in Combination Therapies in Small Cell Lung Cancer.","authors":"Antonio Calles, Emiliano Calvo, Gema Santamaría Nuñez, Federico Costanzo, María José Guillén, Marta Martinez Diez, Aparna Gupta, Carmen Cuevas, Jean-Marc Egly, Pablo Avilés","doi":"10.1158/1535-7163.MCT-24-0050","DOIUrl":"10.1158/1535-7163.MCT-24-0050","url":null,"abstract":"<p><p>Lurbinectedin is a selective inhibitor of oncogenic transcription approved for the treatment of adult patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy. Preclinical data provide evidence for lurbinectedin exerting its actions in a unique manner that involves oncogenic transcription inhibition, DNA damage, reshaping of the tumor microenvironment, and inducing anticancer immunity. Understanding the mechanism of action has facilitated the rational combination of lurbinectedin and anticancer therapies with complementary modes of action, in order to obtain synergistic effects that could potentially lead to improved efficacy. This review evaluates the mechanism of action for lurbinectedin and provides an overview of the therapeutic landscape with regards to lurbinectedin combination therapies for the treatment of small cell lung cancer based on data from preclinical and clinical studies.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"828-839"},"PeriodicalIF":5.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142786149","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":"Targeting CDK7 Enhances the Antitumor Efficacy of Enzalutamide in Androgen Receptor-Positive Triple-Negative Breast Cancer by Inhibiting c-MYC-mediated Tumorigenesis.","authors":"Xuemei Xie, Maroua Manai, Dileep R Rampa, Jon A Fuson, Elizabeth S Nakasone, Troy Pearson, Bharat S Kuntal, Debu Tripathy, Naoto T Ueno, Jangsoon Lee","doi":"10.1158/1535-7163.MCT-23-0386","DOIUrl":"10.1158/1535-7163.MCT-23-0386","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Among TNBC subtypes, the luminal androgen receptor (LAR) subtype expresses high levels of androgen receptor (AR) and generally responds poorly to neoadjuvant chemotherapy. AR has been reported as a promising therapeutic target for the LAR TNBC subtype. In this study, we evaluated the preclinical antitumor efficacy of enzalutamide, an AR inhibitor, in TNBC. Enzalutamide had moderate antiproliferative activity against AR-positive (AR+) TNBC cells (IC50 > 15 μmol/L). To enhance its antitumor efficacy, we performed high-throughput kinome RNAi screening and identified the cell cycle pathway as a potential target. Inhibition of cell cycle progression using the cyclin-dependent kinase 7 inhibitor KRLS-017 showed a synergistic antiproliferative effect with enzalutamide in AR+ LAR MDA-MB-453 and SUM185 TNBC cells. Downstream target analysis revealed that the enzalutamide and KRLS-017 combination dramatically reduced c-MYC expression at both mRNA and protein levels. c-MYC knockdown significantly suppressed growth of MDA-MB-453 and SUM185 cells to a degree comparable with that of enzalutamide and KRLS-017 combination treatment, whereas c-MYC overexpression reversed the synergistic effect. An enhancement in inhibition of tumor growth and suppression of c-MYC expression was further confirmed when enzalutamide was combined with KRLS-017 in an MDA-MB-453 mouse model. Our study suggests that KRLS-017 enhances the antitumor efficacy of enzalutamide by inhibiting c-MYC-mediated tumorigenesis and presents a potential new approach for treating AR+ LAR TNBC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"870-883"},"PeriodicalIF":5.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12104481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716593","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":"Evaluation of VLA-4 (Integrin α4β1) as a Shared Target for Radiopharmaceutical Therapy across Solid Tumors.","authors":"Jeyshka M Reyes-González, Harikrishnan Rajkumar, Woonghee Lee, Kwamena E Baidoo, Robert S Edinger, George Diehl, Divya Nambiar, Reona Okada, Elijah F Edmondson, Stanley Fayn, John Buckley, Ambika P Jaswal, Angel G Cortez, Ian R Marsh, Anders Josefsson, Gary Kohanbash, Jessie R Nedrow, Carolyn J Anderson, Freddy E Escorcia, Rosa Nguyen, Ravi B Patel","doi":"10.1158/1535-7163.MCT-24-0370","DOIUrl":"10.1158/1535-7163.MCT-24-0370","url":null,"abstract":"<p><p>Radiopharmaceutical therapy (RPT) is a promising approach to treating solid tumors, but therapeutic advances are impeded by the lack of broadly expressed targets and shared molecular vulnerability across different tumor types. Here, we evaluate VLA-4 (integrin α4β1) as a potential target for RPT in solid tumors and use radiolabeled copper-64 ([64Cu]Cu-) and copper-67 ([67Cu]Cu-CB-TE1A1P-PEG4-LLP2A) LLP2A, a peptidomimetic ligand of VLA-4, for preclinical imaging and RPT testing. Expression of ITGA4, the gene encoding the alpha 4 subunit (CD49d) of VLA-4, was evaluated in a variety of cancer tissues from publicly available datasets. VLA-4 protein expression was determined by flow cytometry in 22 different human and murine cancer cell lines. We used orthotopic syngeneic (i.e., B16-F10, B78, 4T1, GL261, TH-MYCN, and E2A-PBX1) and human (i.e., SK-MEL-37, 143B, and IMR-5) cancer models for in vivo PET/CT imaging and biodistribution studies. Selected models were used for dosimetry calculations with [64Cu]Cu-LLP2A. To assess in vivo tolerability and efficacy, we performed studies of [67Cu]Cu-LLP2A in tumor-free and B16-F10-bearing C57BL/6J mice (activity range, 0-74 MBq [0-2 mCi]), respectively. We found ITGA4 is overexpressed in hematological malignancies and a variety of solid tumors compared with healthy tissue. VLA-4 was expressed at medium to high levels in 17/22 (77%), at low levels in 4/22 (18%), and negative in 1/22 (5%) tested cell lines. PET/CT imaging with [64Cu]Cu-LLP2A showed tracer uptake in tumors and on-target off-tumor uptake in lymphoid tissues. [67Cu]Cu-LLP2A administered at an activity range of 37 to 74 MBq (1-2 mCi) was tolerated and did not cause long-term hematological or tissue toxicity, except for thymic atrophy. We observed tumor dose response to the activity administered to mice with B16-F10 melanoma. In summary, VLA-4 is broadly expressed across a variety of different cancer tissues and preclinical cancer cell lines, making it a promising target for [67Cu]Cu-LLP2A RPT. With proven on-target on-tumor effect, acceptable toxicity profile, and favorable dosimetry in preclinical models, further investigation of [67Cu]Cu-LLP2A as an RPT agent is warranted.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"896-906"},"PeriodicalIF":5.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255979","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":"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. See related commentary by Buchsbaum, p. 840.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"843-858"},"PeriodicalIF":5.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137021/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Monounsaturated Fatty Acid Metabolism for Radiosensitization of KRAS Mutant 3D Lung Cancer Models.","authors":"Shan Lu, Xiao Pan, Eva Volckova, Anjali Shinde, Schuyler R Fuller, Regina Egan, Jianli Ma, Jong Kung, Christopher J Ott, Aaron N Hata, Cyril H Benes, Jing X Kang, Henning Willers","doi":"10.1158/1535-7163.MCT-24-0213","DOIUrl":"10.1158/1535-7163.MCT-24-0213","url":null,"abstract":"<p><p>Mutations in the KRAS oncogene can mediate resistance to radiation. KRAS mutation-driven tumors have been reported to express cancer stem cell (CSC)-like features and may harbor metabolic liabilities through which CSC-associated radioresistance can be overcome. We established a radiation/drug screening approach that relies on the growth of 3D spheres under anchorage-independent and lipid-limiting culture conditions, which promote stemness and lipogenesis. In this format, we screened 32 KRAS mutation-enriched lung cancer models. As predicted from published data, CB-839, a glutaminase inhibitor, displayed the highest degree of radiosensitization in KRAS mutant models with LKB1 co-mutations. Radiosensitization by inhibition of stearoyl-CoA desaturase-1 (SCD1) displayed a similar genotype preference though the data also implicated KEAP1 co-mutation and SCD1 expression as potential predictors of radiosensitization. In an isogenic model, KRAS mutant cells were characterized by increased SCD1 expression and a higher ratio of monounsaturated fatty acids to saturated fatty acids. Accordingly, pharmacological inhibition or depletion of SCD1 radiosensitized isogenic KRAS mutant but not wild-type cells. The radiosensitizing effect was notably small, especially compared with several DNA repair inhibitors. As an alternative strategy to targeting monounsaturated fatty acid metabolism, adding polyunsaturated fatty acids phenocopied some aspects of SCD1 inhibition, suppressed tumor growth in vivo, and opposed the CSC-like phenotype of KRAS mutant cells. In conclusion, we report a 3D screening approach that recapitulates clinically relevant features of KRAS mutant tumors and can be leveraged for therapeutic targeting of metabolic vulnerabilities. Our data highlight pronounced intertumoral heterogeneity in radiation/drug responses and the complexity of underlying genomic dependencies. See related commentary by Buchsbaum, p. 840.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"920-930"},"PeriodicalIF":5.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008570","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":"Optimization of a novel 2+2 BCMA x CD3 bispecific antibody for minimized cytokine release and potent efficacy.","authors":"Danqing Wu, Lini Huang, Gaowa Naren, Rui Zhang, Shiyong Gong, Xuan Wu, Chengbin Wu","doi":"10.1158/1535-7163.MCT-24-0846","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0846","url":null,"abstract":"<p><p>Cytokine release syndrome remains a critical challenge for clinical use of bispecific T-cell engagers. We present the preclinical development of a novel BCMA x CD3 bispecific antibody with the aim of reducing cytokine release while maintaining potent efficacy in the treatment of multiple myeloma. Based on the Fabs-in-tandem geometry, bispecific molecules with two target arms in cis-configuration were constructed. A panel of anti-CD3 monoclonal antibodies with varying affinities was generated, and the impact of binding arm geometry, valency and anti-CD3 affinity on the TCE's safety and efficacy profile was evaluated both in vitro and in vivo. By comparing with different formats including a reference tandem scFv, we show that both binding arm valency and CD3 affinity determine redirected T-cell cytotoxicity in vitro. The FIT-Ig with 2+2 binding valencies and medium CD3 affinity (CD3med FIT-Ig) can achieve the same potent anti-tumor activity as the reference tandem scFv, while it induced much less cytokine release. Importantly, bivalent CD3 binding does not introduce target irrelevant T-cell activation in the FIT-Ig format. The low cytokine release profile of CD3med FIT-Ig was further validated in human PBMC engrafted mice and cynomolgus monkeys. The CD3med FIT-Ig (also known as EMB-06) could offer a differentiated safety profile with effective anti-tumor activity.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225979","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":"Beyond the Promoter: Total MGMT Gene Methylation Modulates Response to DNA Alkylating Agents in Glioma.","authors":"Nicole J Briceno, Jinkyu Jung, Aiguo Li, Chunzhang Yang, Mioara Larion, Lorinc S Pongor, Fathi Elloumi, Sudhir Varma, William C Reinhold, Yves Pommier, Mark R Gilbert, Orieta Celiku","doi":"10.1158/1535-7163.MCT-24-0977","DOIUrl":"10.1158/1535-7163.MCT-24-0977","url":null,"abstract":"<p><p>Patients with malignant gliomas with methylated MGMT promoters are generally more sensitive to alkylating chemotherapy, as this modification impedes DNA repair. However, inconsistencies in the predictive accuracy of MGMT promoter methylation have been observed. We hypothesize that these variations may be partially explained by a counteracting influence of MGMT gene body methylation. Data from The Cancer Genome Atlas (TCGA) were analyzed to assess correlations between MGMT promoter and body methylation with transcript production across cancer types and within glioma subcohorts. Thirty-six human glioma cell lines underwent molecular profiling via Illumina 850k Methylation Arrays and RNA sequencing. A subset was further tested for MGMT protein levels and carmustine response. Correlations and linear regression analyses were conducted to investigate association of carmustine sensitivity with different levels of MGMT expression. MGMT mRNA expression was positively correlated with body methylation and negatively correlated with promoter methylation across cancers from TCGA. Body and promoter methylation were anticorrelated in the non-glioma cohort and IDH1/2 wild type glioma subcohort but not correlated in the IDH1/2 mutated subcohort. Most glioma cell lines did not express MGMT mRNA. In the cell lines tested for carmustine response, sensitivity was negatively correlated with body methylation and mRNA expression and positively correlated with promoter methylation. Our findings further expound the relationship between MGMT methylation patterns and alkylating agent response, with body methylation playing a significant role. The identified role of gene body methylation underscores the need to integrate the interplay between promoter and body methylation in clinical testing and predicting treatment outcomes.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216376","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":"Enhanced Antitumor Immunity by ASP1570, a Novel Diacylglycerol Kinase ζ Inhibitor, Offers a Potential Novel Immunotherapy for Treating Cancer.","authors":"Osamu Ikeda, Aya Kikuchi, Hirofumi Tsuzuki, Hideyuki Watanabe, Keiichiro Okuyama, Yohei Seki, Satoru Ujihara, Toshihiro Matsuda, Jane Weng, Tomoko Kawashima, Tetsuo Kiso, Atsushi Suzuki, Takeyuki Nagashima, Tomoyuki Suzuki, Kazuya Yamano, Tatsuya Kawase, Taku Yoshida","doi":"10.1158/1535-7163.MCT-23-0108","DOIUrl":"10.1158/1535-7163.MCT-23-0108","url":null,"abstract":"<p><p>Studies of diacylglycerol kinase ζ (DGKζ) in DGKζ knockout mice have revealed its role as an intracellular immune checkpoint in T cells. Although enhancing antitumor immunity by pharmacologic inhibition of DGKζ is desirable, selective DGKζ inhibitors for clinical use remain largely unexplored. In this study, we report a novel, small-molecule DGKζ inhibitor, ASP1570, which is currently under phase 1 development (NCT05083481), and characterize its effect on potential resistance mechanisms against approved immune checkpoint inhibitors in multiple immunosuppressive conditions: not only TGF-β, prostaglandin E2, adenosine, and PD-1 but also cytotoxic T-lymphocyte antigen-4 and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif. First, our findings indicated that ASP1570 exhibited an inhibitory effect on the kinase activity of DGKζ. Unexpectedly, we observed that DGKζ protein was degraded in cells treated with ASP1570 in a proteasome-dependent manner. ASP1570 enhanced T-cell activation with increased diacylglycerol downstream signaling and released anergic T cells from their hyporesponsive state. Furthermore, ASP1570 restored T-cell functions suppressed by multiple immunosuppressive signals (TGF-β, prostaglandin E2, adenosine, PD-1, cytotoxic T-lymphocyte antigen-4, and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif) and induced tumor growth inhibition in two types of syngeneic mouse models: anti-PD-1 antibody-sensitive MC38 and anti-PD-1 antibody-insensitive B16F1/F10. The antitumor efficacy of ASP1570 was canceled by CD8+ T-cell depletion, indicating that its antitumor effect depends on CD8+ cytotoxic T-cell activation. Collectively, ASP1570 potentially improves antitumor efficacy in both anti-PD-1 therapy-resistant and anti-PD-1 therapy-responsive tumors by overcoming multiple immunosuppressive signals.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"884-895"},"PeriodicalIF":5.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730523","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":"RANK pathway inhibition sensitizes triple-negative breast cancer to CDK4/6 inhibitors and enhances immune response.","authors":"Inês Gomes, Maria Martelo, Rúben D Vilela, Maria Jimenez, Eva M Trinidad, Jorge Gómez-Miragaya, Eva González-Suárez, Érica Martins, Sofia S Torres, Patrícia Corredeira, Joana L Miranda, André Mansinho, Sofia Torres, Catarina Abreu, Rita Sousa, Sandra Casimiro, Luís Costa","doi":"10.1158/1535-7163.MCT-24-1158","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-1158","url":null,"abstract":"<p><p>Despite chemotherapy's limitations and toxic effects, it remains the primary treatment for most triple-negative breast cancer (TNBC) patients, with or without immune checkpoint inhibitors (ICI). While cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy have revolutionized luminal BC treatment, CDK4/6i alone are largely ineffective in TNBC, even with functional retinoblastoma protein (pRB). Activation of the receptor activator of nuclear factor-κB (RANK) pathway has been associated with poor prognosis in TNBC and with resistance to CDK4/6i in luminal BC, effects that can be reversed by RANK ligand inhibitors (RANKLi). In this study, we analyzed the effect of RANK knockdown (KD) or RANKLi in the response of pRB-proficient TNBC to CDK4/6i in vitro. RANK+ patient-derived xenograft (PDX) and cell line-derived xenograft models were used to assess therapeutic efficacy of CDK4/6i + RANKLi in vivo. Two syngeneic models of TNBC and luminal BC were used to portrait the main therapy-induced alterations in the tumor immune microenvironment. RANK KD or RANKLi sensitized pRB-proficient TNBC cells to CDK4/6i in vitro. The combination of palbociclib and RANKLi regressed or prevented tumor growth and metastasis in vivo, enhancing cell cycle arrest. Both CDK4/6i and RANKLi elicited an anti-tumor immune response, characterized by an increase in CD4+ and CD8+ T cells and a decrease in tumor-associated macrophage's (TAMs) infiltrating the tumor microenvironment. These findings suggest that combining CDK4/6i and RANKLi could offer a new therapeutic strategy for pRB-proficient TNBC, holding potential immunomodulatory benefits across BC subtypes.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187405","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":"Colony-stimulating factor-1 receptor inhibitor augments osimertinib-induced anti-tumor immunity via suppression of macrophages in lung cancer harboring EGFR mutation.","authors":"Sachi Okawa, Shuta Tomida, Tadahiro Kuribayashi, Jun Nishimura, Takamasa Nakasuka, Atsuko Hirabae, Naofumi Hara, Hirofumi Inoue, Go Makimoto, Kiichiro Ninomiya, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura, Kadoaki Ohashi","doi":"10.1158/1535-7163.MCT-25-0002","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0002","url":null,"abstract":"<p><p>Persister cancer cells, which reversibly adapt to survive epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) treatment, contribute to the incurability of EGFR-mutant lung cancer. We previously reported that gefitinib induces CD8⁺ T cell-related tumor immunity in a genetically engineered mouse model (GEMM). This study investigates the tolerance of persister cancer cells to EGFR-TKI-induced tumor immunity in this model. Egfr-mutated lung cancer cells (C57BL/6/EgfrdelE748-A752) from GEMM were transplanted subcutaneously into wild-type C57BL/6J mice. Persistent tissues under osimertinib treatment were analyzed using digital spatial transcriptional profiling (DSP), immunohistochemical staining (IHC), and flow cytometry (FCM). The anti-tumor effect of osimertinib peaked at 14 days, leaving a small population of persister cancer cells. The number of PD-1⁺ CD8⁺ cells increased in the tumor microenvironment (TME), and CD8⁺ cell depletion attenuated the anti-tumor effect of osimertinib. DSP revealed upregulated expression of M2 macrophage-related genes in the TME of persister cancer cells. Consistently, IHC and FCM confirmed an increased number of CD206⁺ macrophages in the TME. Combining osimertinib with the colony-stimulating factor-1 receptor (CSF1R) inhibitor pexidartinib reduced CD206⁺ macrophages and enhanced the efficacy of osimertinib. Elevated granzyme or CD107 expression on CD8⁺ cells in the TME suggests that macrophages negatively affect osimertinib-induced anti-tumor immunity. M2-like macrophages may contribute to immune tolerance of persister cancer cells against EGFR-TKI-induced tumor immunity. A clinical trial evaluating combined osimertinib and CSF1R inhibitor therapy is warranted for Egfr-mutated lung cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174201","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}