Molecular Cancer Research最新文献_第2页

Novel metastasis suppressor PI3KC2β is mediated by mTORC1 signalling in breast cancer. 新型转移抑制因子PI3KC2β在乳腺癌中由mTORC1信号介导。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-05-13 DOI: 10.1158/1541-7786.MCR-24-1045

Kanakaraju Manupati, Mingang Hao, Suhua Li, Sushma Maharjan, Jun-Lin Guan

{"title":"Novel metastasis suppressor PI3KC2β is mediated by mTORC1 signalling in breast cancer.","authors":"Kanakaraju Manupati, Mingang Hao, Suhua Li, Sushma Maharjan, Jun-Lin Guan","doi":"10.1158/1541-7786.MCR-24-1045","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-1045","url":null,"abstract":"HER2 amplification or mutation accounts for 25% of breast cancer patients that can advance to metastatic disease. Therefore, it is important to identify novel genes which mediate metastasis in HER2+ breast cancer. Here, we describe a new metastatic suppressor gene, Class II phosphatidylinositol 3-kinases (Pik3c2b), by in vivo CRISPR-Cas9 library screening of a custom designed library targeting genes implicated in autophagy using murine HER2+ breast cancer (N418) cells. We further showed that PI3KC2β KO N418 cells increased their migration and invasion in vitro, and lung metastasis in both spontaneous and experimental metastasis assays in vivo. Analysis of breast cancer patient database and tissue samples correlated lower expression of PI3KC2β with decreased metastasis, overall and relapse-free survival. Further, PI3KC2β deletion induced activation of mTORC1 signalling, independent of affecting its kinase activity. Mechanistically, we found that PI3KC2β forms a complex with ITSN1 and raptor that could decreasing stability of raptor, and deletion of either PI3KC2β or ITSN1 led to increased raptor levels and mTORC1 signalling. Lastly, rapamycin treatment reduced migration and invasion of PI3KC2β KO tumor cells in vitro and their lung metastasis in vivo, supporting an important role of mTORC1 pathway. Together, our results identify PI3KC2β as a suppressor for HER2+ breast cancer metastasis by negatively regulating mTORC1 signalling by affecting its complex formation with ITSN1 and raptor. Implications: Our findings revealed PI3KC2β as a new metastasis suppressor for HER2+ breast cancer, which might serve as a potential diagnostic and therapeutic target for the disease.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991171","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}

引用次数: 0

PKCδ regulates DNA damage and cell death through a SIRT6/Nrf2-dependent antioxidant response. PKCδ通过SIRT6/ nrf2依赖的抗氧化反应调节DNA损伤和细胞死亡。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-05-13 DOI: 10.1158/1541-7786.MCR-24-0805

Trisiani Affandi, Angela M Ohm, Jordan T Speidel, M Cecilia Caino, Dillon P Boulton, Mary E Reyland

{"title":"PKCδ regulates DNA damage and cell death through a SIRT6/Nrf2-dependent antioxidant response.","authors":"Trisiani Affandi, Angela M Ohm, Jordan T Speidel, M Cecilia Caino, Dillon P Boulton, Mary E Reyland","doi":"10.1158/1541-7786.MCR-24-0805","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0805","url":null,"abstract":"Protein kinase C delta (PKCδ) regulates DNA repair and apoptosis, and inhibition of PKCδ provides robust radioprotection. Here we show that depletion of PKCδ increases mitochondrial ROS production and induces an endogenous antioxidant response through Nrf2, resulting in decreased basal and irradiation-induced DNA damage and cell death. Radioprotection by PKCδ depletion can be reversed with the free radical scavenger, N-acetyl-L-cysteine, indicating an essential role for the antioxidant response. While mitochondrial mass and membrane potential are increased in PKCδ-depleted cells, oxidative phosphorylation and the activity of electron transport chain (ETC) Complex I and Complex III are reduced, suggesting that ETC dysfunction is the source of the increased mitochondrial ROS. The antioxidant response induced by PKCδ depletion is mediated through Sirtuin 6 (SIRT6) and Nrf2. Increased mitochondrial ROS and Nrf2 activation are reversed in PKCδ/SIRT6 double knockdown cells, indicating a central role for SIRT6 in PKCδ-regulated DNA repair and cell death. Regulation of the endogenous antioxidant state through manipulation of the PKCδ/SIRT6 signaling pathway may be a novel clinical approach for protection of healthy tissues in patients undergoing irradiation therapy. Implications: Regulation of the endogenous antioxidant state through manipulation of the PKCδ/SIRT6 signaling pathway may be a novel clinical approach for protection of healthy tissues in patients undergoing irradiation therapy.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005819","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}

引用次数: 0

METTL3 promotes gastric cancer progression via modulation of FNTA-mediated KRAS/ERK signaling activation. METTL3通过调控fnta介导的KRAS/ERK信号激活促进胃癌进展。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-05-12 DOI: 10.1158/1541-7786.MCR-24-1168

Fangqi Hu, Song Zhang, Jie Chai

{"title":"METTL3 promotes gastric cancer progression via modulation of FNTA-mediated KRAS/ERK signaling activation.","authors":"Fangqi Hu, Song Zhang, Jie Chai","doi":"10.1158/1541-7786.MCR-24-1168","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-1168","url":null,"abstract":"As a vital form of post-transcriptional modification, RNA N6-methyladenosine methylation (m6A) dysregulation is usually associated with the pathogenesis of a range of diseases, including cancer, but the function and underlying mechanisms of m6A in regulating gastric cancer initiation and progression are still poorly understood. Here, we have found methytransferase like 3 (METTL3) and the level of RNA m6A modification were significantly upregulated in gastric cancerous tissues relative to their normal counterparts. In addition, higher METTL3 expression always predicted poorer outcomes for patients with gastric cancer. Methylated RNA sequencing revealed that METTL3 deposited m6A modification on FNTA (farnesyltransferase, subunit alpha) mRNA and accelerated its translation relying on YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) recognition. When METTL3 or FNTA expression was silenced in gastric cancer cells, the FNTA-mediated KRAS plasma membrane distribution was disrupted, resulting in downstream MEK/ERK signaling inactivation, which finally contributed to gastric cancer suppression in vitro and in vivo. In summary, our studies revealed a crosstalk between METTL3-mediated RNA methylation and FNTA-mediated protein modification which synergized to drive gastric cancer progression through orchestrating KRAS/ERK signaling activity. Implications: Targeting METTL3/FNTA pathway will provide an alternative to overcome the resistance of gastric cancer to canonical KRAS inhibitors.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002697","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}

引用次数: 0

PAX8 Interacts with the SWI/SNF Complex at Enhancers to Drive Proliferation in Ovarian Cancer. PAX8与SWI/SNF复合物增强子相互作用，促进卵巢癌的增殖。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-05-02 DOI: 10.1158/1541-7786.MCR-24-0710

Kostianna Sereti, Anna E Russo, Ryan Raisner, Taylur P Ma, Karen E Gascoigne

{"title":"PAX8 Interacts with the SWI/SNF Complex at Enhancers to Drive Proliferation in Ovarian Cancer.","authors":"Kostianna Sereti, Anna E Russo, Ryan Raisner, Taylur P Ma, Karen E Gascoigne","doi":"10.1158/1541-7786.MCR-24-0710","DOIUrl":"10.1158/1541-7786.MCR-24-0710","url":null,"abstract":"Activation of lineage-specific gene expression programs is mediated by the recruitment of lineage-specific transcription factors and their coactivators to chromatin. The lineage factor PAX8 drives essential gene expression in ovarian cancer cells and is required for tumor proliferation. However, the molecular details surrounding cofactor recruitment and specific activation of transcription by PAX8 remain unknown. Here, we identify an important functional interaction between PAX8 and the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. We show that PAX8 can recruit SWI/SNF complexes to DNA, in which they function to open chromatin and facilitate the expression of PAX8 target genes. Genetic deletion of PAX8 results in loss of SWI/SNF from PAX8-bound enhancers, loss of expression of associated target genes, and reduced proliferation. These results can be phenocopied by pharmacological inhibition of SWI/SNF ATPase activity. These data indicate that PAX8 mediates the expression of an essential ovarian cancer proliferative program in part by the recruitment of the SWI/SNF complex, highlighting a novel vulnerability in PAX8-dependent ovarian cancer. Implications: PAX8 recruits SWI/SNF complexes to enhancers to mediate the expression of genes essential for ovarian cancer proliferation.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"416-425"},"PeriodicalIF":4.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365295","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}

引用次数: 0

Epigenetic Dysregulation of Retrotransposons in Cancer. 癌症中反转录转座子的表观遗传失调。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-05-02 DOI: 10.1158/1541-7786.MCR-24-0744

Kwok Yu Liu, Danny Leung

引用次数: 0

RNF6 Inhibits Lung Adenocarcinoma Cell Proliferation by Promoting Cyclin D2 Degradation. RNF6通过促进细胞周期蛋白D2降解抑制肺腺癌细胞增殖。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-05-02 DOI: 10.1158/1541-7786.MCR-24-0703

Yuening Sun, Liyang Jiang, Zubin Zhang, Rongrong Zhu, Jingpei Liang, Ziyang Liu, Yuanming He, Zhenqian Huang, Chunhua Ling, Xiumin Zhou, Xinliang Mao

{"title":"RNF6 Inhibits Lung Adenocarcinoma Cell Proliferation by Promoting Cyclin D2 Degradation.","authors":"Yuening Sun, Liyang Jiang, Zubin Zhang, Rongrong Zhu, Jingpei Liang, Ziyang Liu, Yuanming He, Zhenqian Huang, Chunhua Ling, Xiumin Zhou, Xinliang Mao","doi":"10.1158/1541-7786.MCR-24-0703","DOIUrl":"10.1158/1541-7786.MCR-24-0703","url":null,"abstract":"The E3 ubiquitin ligase RING finger protein 6 (RNF6) has been widely recognized for its role in promoting tumorigenesis in multiple cancers. However, we found that it is downregulated in lung adenocarcinoma (LUAD), and the molecular rationale for this discrepancy remains unclear. In the present study, we find that RNF6, but not its ΔRING inactive form, inhibits LUAD cell proliferation and migration and sensitizes LUAD to chemotherapy. To understand the molecular mechanism, we utilize affinity purification/tandem mass spectrometry (MS-MS) to analyze RNF6-interacting proteins and find that cyclin D2 (CCND2), a key regulator of the G1-S transition in the cell cycle. RNF6 physically binds to CCND2 and mediates its K48-linked polyubiquitination and subsequent degradation. However, ΔRING RNF6 fails to mediate CCND2 for ubiquitination and degradation. Moreover, Thr280 is critically important for CCND2 stability. When Thr280 is mutated, CCND2 becomes more stable and less ubiquitinated by RNF6. Furthermore, RNF6 arrests LUAD cell cycle at the G1 phase by inhibiting the CCND2/phospho-Rb signaling pathway, which is consistent with decreased cell proliferation. Lastly, RNF6 curtails the growth of LUAD xenografts in vivo, associated with decreased CCND2 expression. Therefore, RNF6 is a novel E3 ligase of CCND2 and suppresses LUAD cell proliferation. Implications: This study reveals a novel regulation on cell-cycle transition in LUAD and suggests the RNF6/CCND2 axis may represent an alternative therapeutic target for the treatment of LUAD.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"426-437"},"PeriodicalIF":4.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365296","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}

引用次数: 0

Exome Sequencing Reveals a Sparse Genomic Landscape in Kaposi Sarcoma. 外显子组测序揭示了卡波西肉瘤的稀疏基因组景观。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-05-02 DOI: 10.1158/1541-7786.MCR-24-0373

Warren Phipps, Bhavneet Bhinder, Andrea Towlerton, Peter Mooka, James Kafeero, Matt Fitzgibbon, Olivier Elemento, Ethel Cesarman

{"title":"Exome Sequencing Reveals a Sparse Genomic Landscape in Kaposi Sarcoma.","authors":"Warren Phipps, Bhavneet Bhinder, Andrea Towlerton, Peter Mooka, James Kafeero, Matt Fitzgibbon, Olivier Elemento, Ethel Cesarman","doi":"10.1158/1541-7786.MCR-24-0373","DOIUrl":"10.1158/1541-7786.MCR-24-0373","url":null,"abstract":"Kaposi sarcoma is a frequently aggressive malignancy caused by Kaposi sarcoma herpesvirus. People with immunodeficiencies, including human immunodeficiency virus (HIV), are at increased risk for developing Kaposi sarcoma, but our understanding of the contributions of the cellular genome to Kaposi sarcoma pathogenesis remains limited. To determine if there are cellular genetic alterations in Kaposi sarcoma that might provide biological or therapeutic insights, we performed whole-exome sequencing on 78 Kaposi sarcoma tumors and matched normal control skin from 59 adults with Kaposi sarcoma (46 with HIV-associated Kaposi sarcoma and 13 with HIV-negative Kaposi sarcoma) receiving treatment at the Uganda Cancer Institute in Kampala, Uganda. We found a very low mutational burden in all but one specimen (median = 11 mutations), which is the lowest number of mutations among all 33 tumor types in The Cancer Genome Atlas. No recurrent mutations were seen, and the most commonly affected oncogenic pathway was RTK/RAS. Mutational signatures included defective DNA mismatch repair and smoking. There was no evidence suggesting that multiple tumors from the same patient originated from the same original clone. The number of genome copy alterations per genome was higher in tumors from those without HIV infection and in tumors from participants with advanced stage disease, suggesting that lesions that take longer to develop may accumulate more alterations, although the number of alterations remains low compared with other cancers. Implications: Our findings indicate that the pathogenesis of Kaposi sarcoma differs from other malignancies and that the primary driver of carcinogenesis is Kaposi sarcoma-associated herpesvirus infection and expression of viral oncogenes, rather than clonal oncogenic transformation.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"438-449"},"PeriodicalIF":4.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066574","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}

引用次数: 0

Kindlin-2-Mediated Hematopoiesis Remodeling Regulates Triple-Negative Breast Cancer Immune Evasion. kindlin -2介导的造血重塑调节三阴性乳腺癌免疫逃避。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-05-02 DOI: 10.1158/1541-7786.MCR-24-0698

Wei Wang, Rahul Chaudhary, Justin Szpendyk, Lamyae El Khalki, Neelum Aziz Yousafzai, Ricky Chan, Amar Desai, Khalid Sossey-Alaoui

{"title":"Kindlin-2-Mediated Hematopoiesis Remodeling Regulates Triple-Negative Breast Cancer Immune Evasion.","authors":"Wei Wang, Rahul Chaudhary, Justin Szpendyk, Lamyae El Khalki, Neelum Aziz Yousafzai, Ricky Chan, Amar Desai, Khalid Sossey-Alaoui","doi":"10.1158/1541-7786.MCR-24-0698","DOIUrl":"10.1158/1541-7786.MCR-24-0698","url":null,"abstract":"Triple-negative breast cancer (TNBC) presents significant clinical challenges because of its limited treatment options and aggressive behavior, often associated with poor prognosis. This study focuses on kindlin-2, an adapter protein, and its role in TNBC progression, particularly in hematopoiesis-mediated immune evasion. TNBC tumors expressing high levels of kindlin-2 induce a notable reshaping of hematopoiesis, promoting the expansion of myeloid cells in the bone marrow and spleen. This shift correlated with increased levels of neutrophils and monocytes in tumor-bearing mice over time. Conversely, genetic knockout (KO) of kindlin-2 mitigated this myeloid bias and fostered T-cell infiltration within the tumor microenvironment, indicating the pivotal role of kindlin-2 in immune modulation. Further investigations revealed that kindlin-2 deficiency led to reduced expression of PD-L1, a critical immune checkpoint inhibitor, in TNBC tumors. This molecular change sensitized kindlin-2-deficient tumors to host antitumor immune responses, resulting in enhanced tumor suppression in immunocompetent mouse models. Single-cell RNA sequencing, bulk RNA sequencing, and IHC data supported these findings by highlighting enriched immune-related pathways and increased infiltration of immune cells in kindlin-2-deficient tumors. Therapeutically, targeting PD-L1 in kindlin-2-expressing TNBC tumors effectively inhibited tumor growth, akin to the effects observed with genetic kindlin-2 KO or PD-L1 KO. Our data underscore kindlin-2 as a promising therapeutic target in combination with immune checkpoint blockade to bolster antitumor immunity and counteract resistance mechanisms typical of TNBC and other immune-evasive solid tumors. Implications: Kindlin-2 regulates tumor immune evasion through the systemic modulation of hematopoiesis and PD-L1 expression, which warrants therapeutic targeting of kindlin-2 in patients with TNBC.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"450-462"},"PeriodicalIF":4.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365293","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}

引用次数: 0

Identifying and Targeting Key Driver Genes for Collagen Production within the 11q13/14 Breast Cancer Amplicon. 鉴定和靶向11q13/14乳腺癌扩增子中胶原蛋白产生的关键驱动基因。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-05-02 DOI: 10.1158/1541-7786.MCR-24-0331

Daniela Araiza-Olivera, Tatiana Y Prudnikova, Cristina Uribe-Alvarez, Kathy Q Cai, Janusz Franco-Barraza, Jesus M Dones, Ronald T Raines, Jonathan Chernoff

{"title":"Identifying and Targeting Key Driver Genes for Collagen Production within the 11q13/14 Breast Cancer Amplicon.","authors":"Daniela Araiza-Olivera, Tatiana Y Prudnikova, Cristina Uribe-Alvarez, Kathy Q Cai, Janusz Franco-Barraza, Jesus M Dones, Ronald T Raines, Jonathan Chernoff","doi":"10.1158/1541-7786.MCR-24-0331","DOIUrl":"10.1158/1541-7786.MCR-24-0331","url":null,"abstract":"Breast cancers of the Integrative Cluster 2 (IntClust-2) type, characterized by amplification of a small portion of chromosome 11, have a median survival of only 5 years. Several cancer-relevant genes occupy this portion of chromosome 11, and it is thought that overexpression of a combination of driver genes in this region is responsible for the poor outcome of women in this group. In this study, we used a gene editing method to knock out, one by one, each of the 198 genes that are located within the amplified region of chromosome 11 and determined how much each of these genes contributed to the survival of breast cancer cells. In addition to well-known drivers such as CCND1 and PAK1, we identified two different genes (SERPINH1 and P4HA3) that encode proteins involved in collagen synthesis and organization. Using both in vitro and in vivo functional analyses, we determined that P4HA3 and/or SERPINH1 provide a critical driver function for IntClust-2 basic processes, such as viability, proliferation, and migration. Inhibiting these enzymes via genetic or pharmacologic means reduced collagen synthesis and impeded oncogenic signaling transduction in cell culture models, and a small-molecule inhibitor of P4HA3 was effective in treating 11q13 tumor growth in an animal model. As collagen has a well-known association with tissue stiffness and aggressive forms of breast cancer, we believe that the two genes we identified provide an opportunity for a new therapeutic strategy in IntClust-2 breast cancers. Implications: Breast cancers with 11q13/14 chromosomal amplifications may be vulnerable to inhibitors of collagen synthesis.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"405-415"},"PeriodicalIF":4.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008965","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}

引用次数: 0

Exploiting YES1-Driven EGFR Expression Improves the Efficacy of EGFR Inhibitors. 利用yes1驱动的EGFR表达可提高EGFR抑制剂的疗效。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-05-02 DOI: 10.1158/1541-7786.MCR-24-0309

Leslie Cuellar-Vite, Elyse M Donaubauer, Kristen L Weber-Bonk, Jessica R Bobbitt, Natasha N Ingles, Taylor L Brzozowski, Fadi W Abdul-Karim, Christine N Booth, Ruth A Keri

{"title":"Exploiting YES1-Driven EGFR Expression Improves the Efficacy of EGFR Inhibitors.","authors":"Leslie Cuellar-Vite, Elyse M Donaubauer, Kristen L Weber-Bonk, Jessica R Bobbitt, Natasha N Ingles, Taylor L Brzozowski, Fadi W Abdul-Karim, Christine N Booth, Ruth A Keri","doi":"10.1158/1541-7786.MCR-24-0309","DOIUrl":"10.1158/1541-7786.MCR-24-0309","url":null,"abstract":"EGFR is a highly expressed driver of many cancers, yet the utility of EGFR inhibitors (EGFRi) is limited to cancers that harbor sensitizing mutations in the EGFR gene because of dose-limiting toxicities. Rather than conventionally blocking the kinase activity of EGFR, we sought to reduce its transcription as an alternative approach to broaden the therapeutic window for EGFR inhibitors targeting wild-type (WT) or mutant EGFR. We found that YES1 is highly expressed in triple-negative breast cancer (TNBC) and drives cell growth by elevating EGFR levels. Mechanistically, YES1 stimulates EGFR expression by signaling to JNK and stabilizing the AP-1 transcription factor c-Jun. This effect extends beyond TNBC as YES1 also sustains EGFR expression in non-small cell lung cancer cells, including those that harbor the EGFR gatekeeper mutation T790M. The novel ability of YES1 to regulate the expression of WT and mutant EGFR mRNA and protein provides a potential therapeutic opportunity of utilizing YES1 blockade to broadly increase the efficacy of EGFR inhibitors. Indeed, we observed synergy within in vitro and in vivo models of TNBC and non-small cell lung cancer, even in the absence of EGFR-activating mutations. Together, these data provide a rationale for blocking YES1 activity as an approach for improving the efficacy of EGFR-targeting drugs in cancers that have generally been refractory to such inhibitors. Implications: YES1 sustains EGFR expression, revealing a therapeutic vulnerability for increasing the efficacy of EGFR inhibitors by lowering the threshold for efficacy in tumors driven by the WT or mutant receptor.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"391-404"},"PeriodicalIF":4.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028909","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}

引用次数: 0