Pub Date : 2026-01-05DOI: 10.1038/s43018-025-01102-1
Paolo Strati, Lori Leslie, Parveen Shiraz, Lihua E Budde, Olalekan O Oluwole, Matthew Ulrickson, Aravind Ramakrishnan, Teresa Zhang, Jennifer Sun, Francesca Milletti, Justyna Kanska, Rhine Shen, Frank Neumann, Hairong Xu, Krish Patel
CD19-negative relapse occurs in ~30% of persons with relapsed or refractory large B cell lymphoma (LBCL) who respond to axicabtagene ciloleucel (axi-cel; CD19-directed chimeric antigen receptor (CAR) T cell therapy). In this phase 2 single-arm study, 26 participants with chemorefractory LBCL received axi-cel in combination with rituximab. The primary endpoint was investigator-assessed complete response rate; select secondary endpoints included duration of response (DOR), axi-cel pharmacokinetics and safety. The complete response rate was 73%. Median DOR was 26.0 months; 46% of participants had an ongoing response at data cutoff. Peak CAR T cell (normalized by tumor burden) and rituximab area-under-the-curve levels were elevated in participants with complete or ongoing response. Axi-cel plus rituximab treatment led to durable responses with no new safety signals despite persistent B cell aplasia and pharmacokinetics of axi-cel were unaffected, indicating that dual targeting of CD19 and CD20 is a feasible and safe approach to potentially limit antigen escape. ClinicalTrials.gov registration: NCT04002401 .
{"title":"Axicabtagene ciloleucel in combination with rituximab for refractory large B cell lymphoma: the phase 2, single-arm ZUMA-14 trial.","authors":"Paolo Strati, Lori Leslie, Parveen Shiraz, Lihua E Budde, Olalekan O Oluwole, Matthew Ulrickson, Aravind Ramakrishnan, Teresa Zhang, Jennifer Sun, Francesca Milletti, Justyna Kanska, Rhine Shen, Frank Neumann, Hairong Xu, Krish Patel","doi":"10.1038/s43018-025-01102-1","DOIUrl":"https://doi.org/10.1038/s43018-025-01102-1","url":null,"abstract":"<p><p>CD19-negative relapse occurs in ~30% of persons with relapsed or refractory large B cell lymphoma (LBCL) who respond to axicabtagene ciloleucel (axi-cel; CD19-directed chimeric antigen receptor (CAR) T cell therapy). In this phase 2 single-arm study, 26 participants with chemorefractory LBCL received axi-cel in combination with rituximab. The primary endpoint was investigator-assessed complete response rate; select secondary endpoints included duration of response (DOR), axi-cel pharmacokinetics and safety. The complete response rate was 73%. Median DOR was 26.0 months; 46% of participants had an ongoing response at data cutoff. Peak CAR T cell (normalized by tumor burden) and rituximab area-under-the-curve levels were elevated in participants with complete or ongoing response. Axi-cel plus rituximab treatment led to durable responses with no new safety signals despite persistent B cell aplasia and pharmacokinetics of axi-cel were unaffected, indicating that dual targeting of CD19 and CD20 is a feasible and safe approach to potentially limit antigen escape. ClinicalTrials.gov registration: NCT04002401 .</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-05DOI: 10.1038/s43018-025-01063-5
A phase 2 trial demonstrates that cryoablation followed by sintilimab (an anti-PD1 antibody) and lenvatinib yields a 75% objective response rate in chemotherapy-refractory advanced or metastatic intrahepatic cholangiocarcinoma. Multi-omics analyses reveal that enhanced immunogenicity and lymphocyte infiltration underpin the abscopal effect.
{"title":"Cryoablation induces abscopal immunity in intrahepatic cholangiocarcinoma","authors":"","doi":"10.1038/s43018-025-01063-5","DOIUrl":"10.1038/s43018-025-01063-5","url":null,"abstract":"A phase 2 trial demonstrates that cryoablation followed by sintilimab (an anti-PD1 antibody) and lenvatinib yields a 75% objective response rate in chemotherapy-refractory advanced or metastatic intrahepatic cholangiocarcinoma. Multi-omics analyses reveal that enhanced immunogenicity and lymphocyte infiltration underpin the abscopal effect.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"12-13"},"PeriodicalIF":28.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-05DOI: 10.1038/s43018-025-01096-w
Andrea Pérez González, Cédric Blanpain
Dormant metastases can lead to tumor relapse after many years by successfully escaping immune surveillance. A new study identifies an atypical epithelial-to-mesenchymal transition state that presents low stiffness mediated by actin depolymerization, which prevents immune cell-mediated killing of dormant metastatic lung adenocarcinoma.
{"title":"Cell stiffness regulates immune evasion during metastatic dormancy","authors":"Andrea Pérez González, Cédric Blanpain","doi":"10.1038/s43018-025-01096-w","DOIUrl":"10.1038/s43018-025-01096-w","url":null,"abstract":"Dormant metastases can lead to tumor relapse after many years by successfully escaping immune surveillance. A new study identifies an atypical epithelial-to-mesenchymal transition state that presents low stiffness mediated by actin depolymerization, which prevents immune cell-mediated killing of dormant metastatic lung adenocarcinoma.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"1-3"},"PeriodicalIF":28.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-05DOI: 10.1038/s43018-025-01066-2
Oncogenic KRAS hijacks chromatin remodeling during pancreatitis-induced tissue regeneration to drive tumorigenesis. We found that the chromatin remodeler SMARCA5 cooperates with oncogenic KRAS to maintain the malignant chromatin state; its deletion blocked tumorigenesis while preserving pancreatic tissue repair.
{"title":"Loss of SMARCA5 redirects pancreatic tumorigenesis toward a regenerative cell fate","authors":"","doi":"10.1038/s43018-025-01066-2","DOIUrl":"10.1038/s43018-025-01066-2","url":null,"abstract":"Oncogenic KRAS hijacks chromatin remodeling during pancreatitis-induced tissue regeneration to drive tumorigenesis. We found that the chromatin remodeler SMARCA5 cooperates with oncogenic KRAS to maintain the malignant chromatin state; its deletion blocked tumorigenesis while preserving pancreatic tissue repair.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"14-15"},"PeriodicalIF":28.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-05DOI: 10.1038/s43018-025-01087-x
Rebecca A. Burrell, Sanjeev Kumar, Elena Provenzano, Cleopatra Pike, Alimu Dayimu, Stuart A. McIntosh, Vassilis Pitsinis, Polly King, Beatrix Elsberger, Sasi Govindarajulu, Lucy Satherley, Sirwan Hadad, Peter Schmid, Amit Agrawal, Bodiere Akpuluma, Steven Bell, John R. Benson, Carlos Caldas, Danya Cheeseman, Igor Chernukhin, Parto Forouhi, Tulay Gulsen, Eleftheria Kleidi, Karen Pinilla, Wendi Qian, Jean E. Abraham, Jason S. Carroll, Richard D. Baird
The use of progestogens in breast cancer has been controversial. Recent preclinical studies have shown that ligand-bound progesterone receptor interacts directly with the estrogen receptor (ER) and reprograms ER transcriptional activity. Progestogen cotreatment enhances the antitumor activity of antiestrogen therapy in mouse xenografts. We report PIONEER, a 198-participant, three-arm, randomized phase 2b window-of-opportunity study for women with early-stage ER+ breast cancer, which evaluated letrozole with or without megestrol at 40 mg or 160 mg daily. The primary endpoint was the change in tumor proliferation measured by Ki67 immunohistochemistry. Secondary and exploratory endpoints included a comparison of low versus higher dose of megestrol, safety, tolerability and biomarker subgroup analyses. The trial met its primary endpoint, with a greater reduction in proliferation seen when megestrol was added to letrozole. This effect was accompanied by reduced ER genomic binding at canonical binding sites in paired tumor biopsies, indicating reduced ER transcriptional activity. These results support further evaluation of low-dose megestrol, which has two mechanisms for potentially improving breast cancer outcomes in combination with standard antiestrogen therapy: alleviating hot flashes and thereby helping with treatment adherence, as well as a direct antiproliferative effect ( NCT03306472 ). Baird et al. present the phase 2 PIONEER trial findings on the antitumor activity of combining aromatase inhibitor letrozole with megestrol in postmenopausal women with operable estrogen-receptor-positive human epidermal-growth-factor-receptor-2-negative breast cancer.
{"title":"Evaluating progesterone receptor agonist megestrol plus letrozole for women with early-stage estrogen-receptor-positive breast cancer: the window-of-opportunity, randomized, phase 2b, PIONEER trial","authors":"Rebecca A. Burrell, Sanjeev Kumar, Elena Provenzano, Cleopatra Pike, Alimu Dayimu, Stuart A. McIntosh, Vassilis Pitsinis, Polly King, Beatrix Elsberger, Sasi Govindarajulu, Lucy Satherley, Sirwan Hadad, Peter Schmid, Amit Agrawal, Bodiere Akpuluma, Steven Bell, John R. Benson, Carlos Caldas, Danya Cheeseman, Igor Chernukhin, Parto Forouhi, Tulay Gulsen, Eleftheria Kleidi, Karen Pinilla, Wendi Qian, Jean E. Abraham, Jason S. Carroll, Richard D. Baird","doi":"10.1038/s43018-025-01087-x","DOIUrl":"10.1038/s43018-025-01087-x","url":null,"abstract":"The use of progestogens in breast cancer has been controversial. Recent preclinical studies have shown that ligand-bound progesterone receptor interacts directly with the estrogen receptor (ER) and reprograms ER transcriptional activity. Progestogen cotreatment enhances the antitumor activity of antiestrogen therapy in mouse xenografts. We report PIONEER, a 198-participant, three-arm, randomized phase 2b window-of-opportunity study for women with early-stage ER+ breast cancer, which evaluated letrozole with or without megestrol at 40 mg or 160 mg daily. The primary endpoint was the change in tumor proliferation measured by Ki67 immunohistochemistry. Secondary and exploratory endpoints included a comparison of low versus higher dose of megestrol, safety, tolerability and biomarker subgroup analyses. The trial met its primary endpoint, with a greater reduction in proliferation seen when megestrol was added to letrozole. This effect was accompanied by reduced ER genomic binding at canonical binding sites in paired tumor biopsies, indicating reduced ER transcriptional activity. These results support further evaluation of low-dose megestrol, which has two mechanisms for potentially improving breast cancer outcomes in combination with standard antiestrogen therapy: alleviating hot flashes and thereby helping with treatment adherence, as well as a direct antiproliferative effect ( NCT03306472 ). Baird et al. present the phase 2 PIONEER trial findings on the antitumor activity of combining aromatase inhibitor letrozole with megestrol in postmenopausal women with operable estrogen-receptor-positive human epidermal-growth-factor-receptor-2-negative breast cancer.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"194-206"},"PeriodicalIF":28.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-025-01087-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906212","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}
Pub Date : 2026-01-05DOI: 10.1038/s43018-025-01084-0
Nils Bessler, Amber K L Wezenaar, Hendrikus C R Ariese, Celina Honhoff, Noëlle Dommann, Ellen J Wehrens, Cristian Ruiz Moreno, Thijs J M van den Broek, Raphaël V U Collot, Daan J Kloosterman, Farid Keramati, Mieke Roosen, Sam de Blank, Esmée van Vliet, Mario Barrera Román, Lucrezia C D E Gatti, Ali Ertürk, Jürgen Kuball, Zsolt Sebestyén, Marcel Kool, Sara Patrizi, Evelina Miele, Annette Künkele, Mariëtte E G Kranendonk, Annelisa M Cornel, Stefan Nierkens, Christian Mayer, Hendrik G Stunnenberg, Anna Alemany, Maria Alieva, Anne C Rios
Diffuse midline glioma (DMG) is a highly aggressive and untreatable pediatric cancer primarily arising in the pontine brainstem region, necessitating the development of representative models for treatment advance. Here we developed an FGF4-driven human brainstem organoid model, which we used to genetically engineer H3.3K27M-altered DMG. We demonstrated that brainstem pontine glial specification is critical for DMG tumorigenesis, yielding infiltrative tumors that recapitulate patient-representative intratumoral heterogeneity. Prolonged GD2 chimeric antigen receptor (CAR) T cell treatment mirrored clinical outcomes and revealed extensive transcriptional heterogeneity, from which both potent effector and dysfunctional CAR T cell populations could be identified. Furthermore, incorporation of myeloid cells generated DMG-specific microglia that reduced treatment efficacy and revealed CAR T cell functional states most vulnerable to microglia-mediated immunosuppression. Thus, we present a representative DMG model offering a months-long experimental window in vitro, which we leveraged to delineate CAR T cell functionality and microglial impact, aiding therapy development for this devastating disease.
{"title":"De novo H3.3K27M-altered diffuse midline glioma in human brainstem organoids to dissect GD2 CAR T cell function.","authors":"Nils Bessler, Amber K L Wezenaar, Hendrikus C R Ariese, Celina Honhoff, Noëlle Dommann, Ellen J Wehrens, Cristian Ruiz Moreno, Thijs J M van den Broek, Raphaël V U Collot, Daan J Kloosterman, Farid Keramati, Mieke Roosen, Sam de Blank, Esmée van Vliet, Mario Barrera Román, Lucrezia C D E Gatti, Ali Ertürk, Jürgen Kuball, Zsolt Sebestyén, Marcel Kool, Sara Patrizi, Evelina Miele, Annette Künkele, Mariëtte E G Kranendonk, Annelisa M Cornel, Stefan Nierkens, Christian Mayer, Hendrik G Stunnenberg, Anna Alemany, Maria Alieva, Anne C Rios","doi":"10.1038/s43018-025-01084-0","DOIUrl":"https://doi.org/10.1038/s43018-025-01084-0","url":null,"abstract":"<p><p>Diffuse midline glioma (DMG) is a highly aggressive and untreatable pediatric cancer primarily arising in the pontine brainstem region, necessitating the development of representative models for treatment advance. Here we developed an FGF4-driven human brainstem organoid model, which we used to genetically engineer H3.3K27M-altered DMG. We demonstrated that brainstem pontine glial specification is critical for DMG tumorigenesis, yielding infiltrative tumors that recapitulate patient-representative intratumoral heterogeneity. Prolonged GD2 chimeric antigen receptor (CAR) T cell treatment mirrored clinical outcomes and revealed extensive transcriptional heterogeneity, from which both potent effector and dysfunctional CAR T cell populations could be identified. Furthermore, incorporation of myeloid cells generated DMG-specific microglia that reduced treatment efficacy and revealed CAR T cell functional states most vulnerable to microglia-mediated immunosuppression. Thus, we present a representative DMG model offering a months-long experimental window in vitro, which we leveraged to delineate CAR T cell functionality and microglial impact, aiding therapy development for this devastating disease.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-05DOI: 10.1038/s43018-025-01094-y
Zhenghan Wang, Yassmin Elbanna, Inês Godet, Siting Gan, Lila Peters, George Lampe, Yanyan Chen, Joao Xavier, Morgan Huse, Joan Massagué
Different forms of epithelial-to-mesenchymal transition (EMT) manifest during tumor progression. Little is known about the mechanistic basis and functional role of these distinct EMTs. We explored this question in lung adenocarcinoma (LUAD) primitive progenitors, which are competent to enter dormancy in response to transforming growth factor-β (TGFβ) upon metastatic dissemination. The TGFβ response in these cells includes growth arrest and a full EMT that subsequently transitions into an atypical mesenchymal state of round morphology and lacking actin stress fibers. TGFβ drives this transition by inducing expression of the actin depolymerizing protein gelsolin, which converts a migratory, stress-fiber-rich phenotype into a cortical actin-rich, spheroidal state. This transition lowers the biomechanical stiffness of metastatic progenitors and protects them from killing by cytotoxic lymphocytes. Gelsolin-deficient LUAD progenitors can enter dormancy but succumb to immune surveillance. Thus, quiescent LUAD metastatic progenitors undergo an atypical EMT to avert immune surveillance during TGFβ-driven metastatic dormancy. Wang et al. report that LUAD cells entering dormancy transition into a TGFβ-induced atypical mesenchymal state characterized by a soft spheroidal morphology and strong EMT signature, which protects disseminated cancer cells from immune clearance.
{"title":"TGFβ induces an atypical EMT to evade immune mechanosurveillance in lung adenocarcinoma dormant metastasis","authors":"Zhenghan Wang, Yassmin Elbanna, Inês Godet, Siting Gan, Lila Peters, George Lampe, Yanyan Chen, Joao Xavier, Morgan Huse, Joan Massagué","doi":"10.1038/s43018-025-01094-y","DOIUrl":"10.1038/s43018-025-01094-y","url":null,"abstract":"Different forms of epithelial-to-mesenchymal transition (EMT) manifest during tumor progression. Little is known about the mechanistic basis and functional role of these distinct EMTs. We explored this question in lung adenocarcinoma (LUAD) primitive progenitors, which are competent to enter dormancy in response to transforming growth factor-β (TGFβ) upon metastatic dissemination. The TGFβ response in these cells includes growth arrest and a full EMT that subsequently transitions into an atypical mesenchymal state of round morphology and lacking actin stress fibers. TGFβ drives this transition by inducing expression of the actin depolymerizing protein gelsolin, which converts a migratory, stress-fiber-rich phenotype into a cortical actin-rich, spheroidal state. This transition lowers the biomechanical stiffness of metastatic progenitors and protects them from killing by cytotoxic lymphocytes. Gelsolin-deficient LUAD progenitors can enter dormancy but succumb to immune surveillance. Thus, quiescent LUAD metastatic progenitors undergo an atypical EMT to avert immune surveillance during TGFβ-driven metastatic dormancy. Wang et al. report that LUAD cells entering dormancy transition into a TGFβ-induced atypical mesenchymal state characterized by a soft spheroidal morphology and strong EMT signature, which protects disseminated cancer cells from immune clearance.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"131-149"},"PeriodicalIF":28.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-025-01094-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906217","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}
Pub Date : 2026-01-02DOI: 10.1038/s43018-025-01081-3
Eric Haines, Michael Burke, Rachel Catterall, Victor De Jesus, Daniel Hidalgo, Bin Li, Joseph D. Manna, Ao Yang, Jill Cavanaugh, Sarah R. Wessell, Marta Sanchez-Martin, Alexander Ivliev, Wilmin Bartolini, Sergio Santillana, Jeffrey Ecsedy, Michelle X. Zhang, Sabine K. Ruppel
MAPK pathway alterations are the most common oncogenic drivers. Among the approved therapies targeting this pathway are RAS, MEK and RAF inhibitors. However, therapeutic resistance and toxicities have limited their clinical success. Here, to overcome these liabilities, we developed IK-595, a potent MEK–RAF molecular glue. IK-595 traps MEK in an inactive complex with all RAF isoforms. In addition, IK-595 precludes CRAF-mediated MEK reactivation and ARAF heterodimerization, allowing for prolonged target engagement and durable MAPK pathway inhibition. This translates into superior antitumor activity across a wide range of cancer model indications harboring MAPK pathway alterations. A key advantage of IK-595 is its ability to achieve transient high plasma exposure affording a larger therapeutic window. The unique mechanism of action and improved tolerability positions IK-595 as an ideal combination partner. IK-595 is an MEK–RAF molecular glue that prolongs pathway inhibition while providing a broader therapeutic window as monotherapy and in combination. Haines et al. developed an MEK–RAF molecular glue called IK-595 that blocks MAPK pathway activation in RAS-mutant and BRAF-mutant cancer cells. IK-595 exhibited high tolerability and strong antitumor effects in preclinical models across cancer types.
{"title":"The MEK–RAF molecular glue IK-595 has potent antitumor activity across RAS/MAPK pathway-altered cancers","authors":"Eric Haines, Michael Burke, Rachel Catterall, Victor De Jesus, Daniel Hidalgo, Bin Li, Joseph D. Manna, Ao Yang, Jill Cavanaugh, Sarah R. Wessell, Marta Sanchez-Martin, Alexander Ivliev, Wilmin Bartolini, Sergio Santillana, Jeffrey Ecsedy, Michelle X. Zhang, Sabine K. Ruppel","doi":"10.1038/s43018-025-01081-3","DOIUrl":"10.1038/s43018-025-01081-3","url":null,"abstract":"MAPK pathway alterations are the most common oncogenic drivers. Among the approved therapies targeting this pathway are RAS, MEK and RAF inhibitors. However, therapeutic resistance and toxicities have limited their clinical success. Here, to overcome these liabilities, we developed IK-595, a potent MEK–RAF molecular glue. IK-595 traps MEK in an inactive complex with all RAF isoforms. In addition, IK-595 precludes CRAF-mediated MEK reactivation and ARAF heterodimerization, allowing for prolonged target engagement and durable MAPK pathway inhibition. This translates into superior antitumor activity across a wide range of cancer model indications harboring MAPK pathway alterations. A key advantage of IK-595 is its ability to achieve transient high plasma exposure affording a larger therapeutic window. The unique mechanism of action and improved tolerability positions IK-595 as an ideal combination partner. IK-595 is an MEK–RAF molecular glue that prolongs pathway inhibition while providing a broader therapeutic window as monotherapy and in combination. Haines et al. developed an MEK–RAF molecular glue called IK-595 that blocks MAPK pathway activation in RAS-mutant and BRAF-mutant cancer cells. IK-595 exhibited high tolerability and strong antitumor effects in preclinical models across cancer types.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"116-130"},"PeriodicalIF":28.5,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-02DOI: 10.1038/s43018-025-01052-8
Evripidis Gavathiotis
RAS–MAPK pathway inhibitors are limited by pathway reactivation and toxicity. A study now introduces IK-595, a MEK–RAF molecular glue that stabilizes MEK in an inactive complex with RAF isoforms, enabling durable inhibition of ERK signaling and anti-tumor activity in various cancers in which RAS or RAF is altered, including those resistant to current standard-of-care therapies.
{"title":"A molecular glue halts RAS–MAPK signaling","authors":"Evripidis Gavathiotis","doi":"10.1038/s43018-025-01052-8","DOIUrl":"10.1038/s43018-025-01052-8","url":null,"abstract":"RAS–MAPK pathway inhibitors are limited by pathway reactivation and toxicity. A study now introduces IK-595, a MEK–RAF molecular glue that stabilizes MEK in an inactive complex with RAF isoforms, enabling durable inhibition of ERK signaling and anti-tumor activity in various cancers in which RAS or RAF is altered, including those resistant to current standard-of-care therapies.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"4-6"},"PeriodicalIF":28.5,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145891867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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