Pub Date : 2024-05-01DOI: 10.1158/2159-8290.CD-23-0700
Tetsuo Tani, Haritha Mathsyaraja, Marco Campisi, Ze-Hua Li, Koji Haratani, Caroline G Fahey, Keiichi Ota, Navin R Mahadevan, Yingxiao Shi, Shin Saito, Kei Mizuno, Tran C Thai, Nobunari Sasaki, Mizuki Homme, Choudhury Fabliha B Yusuf, Adam Kashishian, Jipsa Panchal, Min Wang, Benjamin J Wolf, Thanh U Barbie, Cloud P Paweletz, Prafulla C Gokhale, David Liu, Ravindra Uppaluri, Shunsuke Kitajima, Jennifer Cain, David A Barbie
A substantial fraction of cancers evade immune detection by silencing Stimulator of Interferon Genes (STING)-Interferon (IFN) signaling. Therapeutic reactivation of this program via STING agonists, epigenetic, or DNA-damaging therapies can restore antitumor immunity in multiple preclinical models. Here we show that adaptive induction of three prime exonuclease 1 (TREX1) restrains STING-dependent nucleic acid sensing in cancer cells via its catalytic function in degrading cytosolic DNA. Cancer cell TREX1 expression is coordinately induced with STING by autocrine IFN and downstream STAT1, preventing signal amplification. TREX1 inactivation in cancer cells thus unleashes STING-IFN signaling, recruiting T and natural killer (NK) cells, sensitizing to NK cell-derived IFNγ, and cooperating with programmed cell death protein 1 blockade in multiple mouse tumor models to enhance immunogenicity. Targeting TREX1 may represent a complementary strategy to induce cytosolic DNA and amplify cancer cell STING-IFN signaling as a means to sensitize tumors to immune checkpoint blockade (ICB) and/or cell therapies.
Significance: STING-IFN signaling in cancer cells promotes tumor cell immunogenicity. Inactivation of the DNA exonuclease TREX1, which is adaptively upregulated to limit pathway activation in cancer cells, recruits immune effector cells and primes NK cell-mediated killing. Targeting TREX1 has substantial therapeutic potential to amplify cancer cell immunogenicity and overcome ICB resistance. This article is featured in Selected Articles from This Issue, p. 695.
相当一部分癌症通过抑制 STING(干扰素基因刺激器)-干扰素(IFN)信号传导来逃避免疫检测。通过 STING 激动剂、表观遗传或 DNA 损伤疗法重新激活这一程序,可在多种临床前模型中恢复抗肿瘤免疫力。在这里,我们发现三质子外切酶 1(TREX1)的适应性诱导可通过其降解细胞膜 DNA 的催化功能抑制癌细胞中 STING 依赖性核酸感应。癌细胞 TREX1 的表达与 STING 一起受到自分泌 IFN 和下游 STAT1 的协调诱导,从而阻止了信号的放大。因此,癌细胞中的 TREX1 失活会释放 STING-IFN 信号,招募 T 细胞和 NK(自然杀伤)细胞,对 NK 细胞衍生的 IFNγ 产生敏感性,并在多种小鼠肿瘤模型中与 PD-1 阻断协同作用,增强免疫原性。靶向 TREX1 可能是诱导细胞膜 DNA 和放大癌细胞 STING-IFN 信号的一种补充策略,是使肿瘤对免疫检查点阻断(ICB)和/或细胞疗法敏感的一种手段。
{"title":"TREX1 Inactivation Unleashes Cancer Cell STING-Interferon Signaling and Promotes Antitumor Immunity.","authors":"Tetsuo Tani, Haritha Mathsyaraja, Marco Campisi, Ze-Hua Li, Koji Haratani, Caroline G Fahey, Keiichi Ota, Navin R Mahadevan, Yingxiao Shi, Shin Saito, Kei Mizuno, Tran C Thai, Nobunari Sasaki, Mizuki Homme, Choudhury Fabliha B Yusuf, Adam Kashishian, Jipsa Panchal, Min Wang, Benjamin J Wolf, Thanh U Barbie, Cloud P Paweletz, Prafulla C Gokhale, David Liu, Ravindra Uppaluri, Shunsuke Kitajima, Jennifer Cain, David A Barbie","doi":"10.1158/2159-8290.CD-23-0700","DOIUrl":"10.1158/2159-8290.CD-23-0700","url":null,"abstract":"<p><p>A substantial fraction of cancers evade immune detection by silencing Stimulator of Interferon Genes (STING)-Interferon (IFN) signaling. Therapeutic reactivation of this program via STING agonists, epigenetic, or DNA-damaging therapies can restore antitumor immunity in multiple preclinical models. Here we show that adaptive induction of three prime exonuclease 1 (TREX1) restrains STING-dependent nucleic acid sensing in cancer cells via its catalytic function in degrading cytosolic DNA. Cancer cell TREX1 expression is coordinately induced with STING by autocrine IFN and downstream STAT1, preventing signal amplification. TREX1 inactivation in cancer cells thus unleashes STING-IFN signaling, recruiting T and natural killer (NK) cells, sensitizing to NK cell-derived IFNγ, and cooperating with programmed cell death protein 1 blockade in multiple mouse tumor models to enhance immunogenicity. Targeting TREX1 may represent a complementary strategy to induce cytosolic DNA and amplify cancer cell STING-IFN signaling as a means to sensitize tumors to immune checkpoint blockade (ICB) and/or cell therapies.</p><p><strong>Significance: </strong>STING-IFN signaling in cancer cells promotes tumor cell immunogenicity. Inactivation of the DNA exonuclease TREX1, which is adaptively upregulated to limit pathway activation in cancer cells, recruits immune effector cells and primes NK cell-mediated killing. Targeting TREX1 has substantial therapeutic potential to amplify cancer cell immunogenicity and overcome ICB resistance. This article is featured in Selected Articles from This Issue, p. 695.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11062818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139478027","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 : 2024-05-01DOI: 10.1158/2159-8290.CD-23-0388
Azadeh C Bashi, Elizabeth A Coker, Krishna C Bulusu, Patricia Jaaks, Claire Crafter, Howard Lightfoot, Marta Milo, Katrina McCarten, David F Jenkins, Dieudonne van der Meer, James T Lynch, Syd Barthorpe, Courtney L Andersen, Simon T Barry, Alexandra Beck, Justin Cidado, Jacob A Gordon, Caitlin Hall, James Hall, Iman Mali, Tatiana Mironenko, Kevin Mongeon, James Morris, Laura Richardson, Paul D Smith, Omid Tavana, Charlotte Tolley, Frances Thomas, Brandon S Willis, Wanjuan Yang, Mark J O'Connor, Ultan McDermott, Susan E Critchlow, Lisa Drew, Stephen E Fawell, Jerome T Mettetal, Mathew J Garnett
Oncology drug combinations can improve therapeutic responses and increase treatment options for patients. The number of possible combinations is vast and responses can be context-specific. Systematic screens can identify clinically relevant, actionable combinations in defined patient subtypes. We present data for 109 anticancer drug combinations from AstraZeneca's oncology small molecule portfolio screened in 755 pan-cancer cell lines. Combinations were screened in a 7 × 7 concentration matrix, with more than 4 million measurements of sensitivity, producing an exceptionally data-rich resource. We implement a new approach using combination Emax (viability effect) and highest single agent (HSA) to assess combination benefit. We designed a clinical translatability workflow to identify combinations with clearly defined patient populations, rationale for tolerability based on tumor type and combination-specific "emergent" biomarkers, and exposures relevant to clinical doses. We describe three actionable combinations in defined cancer types, confirmed in vitro and in vivo, with a focus on hematologic cancers and apoptotic targets.
Significance: We present the largest cancer drug combination screen published to date with 7 × 7 concentration response matrices for 109 combinations in more than 750 cell lines, complemented by multi-omics predictors of response and identification of "emergent" combination biomarkers. We prioritize hits to optimize clinical translatability, and experimentally validate novel combination hypotheses. This article is featured in Selected Articles from This Issue, p. 695.
{"title":"Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations.","authors":"Azadeh C Bashi, Elizabeth A Coker, Krishna C Bulusu, Patricia Jaaks, Claire Crafter, Howard Lightfoot, Marta Milo, Katrina McCarten, David F Jenkins, Dieudonne van der Meer, James T Lynch, Syd Barthorpe, Courtney L Andersen, Simon T Barry, Alexandra Beck, Justin Cidado, Jacob A Gordon, Caitlin Hall, James Hall, Iman Mali, Tatiana Mironenko, Kevin Mongeon, James Morris, Laura Richardson, Paul D Smith, Omid Tavana, Charlotte Tolley, Frances Thomas, Brandon S Willis, Wanjuan Yang, Mark J O'Connor, Ultan McDermott, Susan E Critchlow, Lisa Drew, Stephen E Fawell, Jerome T Mettetal, Mathew J Garnett","doi":"10.1158/2159-8290.CD-23-0388","DOIUrl":"10.1158/2159-8290.CD-23-0388","url":null,"abstract":"<p><p>Oncology drug combinations can improve therapeutic responses and increase treatment options for patients. The number of possible combinations is vast and responses can be context-specific. Systematic screens can identify clinically relevant, actionable combinations in defined patient subtypes. We present data for 109 anticancer drug combinations from AstraZeneca's oncology small molecule portfolio screened in 755 pan-cancer cell lines. Combinations were screened in a 7 × 7 concentration matrix, with more than 4 million measurements of sensitivity, producing an exceptionally data-rich resource. We implement a new approach using combination Emax (viability effect) and highest single agent (HSA) to assess combination benefit. We designed a clinical translatability workflow to identify combinations with clearly defined patient populations, rationale for tolerability based on tumor type and combination-specific \"emergent\" biomarkers, and exposures relevant to clinical doses. We describe three actionable combinations in defined cancer types, confirmed in vitro and in vivo, with a focus on hematologic cancers and apoptotic targets.</p><p><strong>Significance: </strong>We present the largest cancer drug combination screen published to date with 7 × 7 concentration response matrices for 109 combinations in more than 750 cell lines, complemented by multi-omics predictors of response and identification of \"emergent\" combination biomarkers. We prioritize hits to optimize clinical translatability, and experimentally validate novel combination hypotheses. This article is featured in Selected Articles from This Issue, p. 695.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":28.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11061612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140058682","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 : 2024-05-01DOI: 10.1158/2159-8290.cd-23-1522
Hamza Celik, Grant A. Challen
Summary: Dunbar, Bowman, and colleagues present here a novel genetic mouse model with inducible and reversible expression of the JAK2V617F mutation in the endogenous locus. Results from this study clearly demonstrate an absolute requirement for myeloproliferative neoplasm–initiating cells for this mutation in their survival and imply that more efficacious inhibitors could be curative for these patients even in the setting of additional cooperating mutations. See related article by Dunbar et al., p. 737 (8).
{"title":"Enhanced Molecular Response in Myeloproliferative Neoplasms with Complete JAK2V617F Inhibition","authors":"Hamza Celik, Grant A. Challen","doi":"10.1158/2159-8290.cd-23-1522","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-23-1522","url":null,"abstract":"Summary: Dunbar, Bowman, and colleagues present here a novel genetic mouse model with inducible and reversible expression of the JAK2V617F mutation in the endogenous locus. Results from this study clearly demonstrate an absolute requirement for myeloproliferative neoplasm–initiating cells for this mutation in their survival and imply that more efficacious inhibitors could be curative for these patients even in the setting of additional cooperating mutations. See related article by Dunbar et al., p. 737 (8).","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":28.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140819360","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 : 2024-05-01DOI: 10.1158/2159-8290.cd-24-0024
Rona Yaeger, Meredith A. McKean, Rizwan Haq, J. Thaddeus Beck, Matthew H. Taylor, Jonathan Eliezer. Cohen, Daniel W. Bowles, Shirish M. Gadgeel, Catalin Mihalcioiu, Kyriakos P. Papadopoulos, Eli L. Diamond, Keren B. Sturtz, Gang Feng, Stefanie K. Drescher, Micaela B. Reddy, Bhaswati Sengupta, Arnab K. Maity, Suzy A. Brown, Anurag Singh, Eric N. Brown, Brian R. Baer, Jim Wong, Tung-Chung Mou, Wen-I Wu, Dean R. Kahn, Sunyana Gadal, Neal Rosen, John J. Gaudino, Patrice A. Lee, Dylan P. Hartley, S. Michael. Rothenberg
RAF inhibitors have transformed treatment for BRAF V600-mutant cancer patients, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAF V600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling. PF-07799933 ± binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAF V600E with acquired resistance to current RAF inhibitors. We treated patients with treatment-refractory BRAF-mutant solid tumors in a first-in-human clinical trial (NCT05355701) that utilized a novel, flexible, pharmacokinetics-informed dose escalation design that allowed rapid achievement of PF-07799933 efficacious concentrations. PF-07799933 ± binimetinib was well-tolerated and resulted in multiple confirmed responses, systemically and in the brain, in BRAF-mutant cancer patients refractory to approved RAF inhibitors.
{"title":"A next-generation BRAF inhibitor overcomes resistance to BRAF inhibition in patients with BRAF-mutant cancers using pharmacokinetics-informed dose escalation","authors":"Rona Yaeger, Meredith A. McKean, Rizwan Haq, J. Thaddeus Beck, Matthew H. Taylor, Jonathan Eliezer. Cohen, Daniel W. Bowles, Shirish M. Gadgeel, Catalin Mihalcioiu, Kyriakos P. Papadopoulos, Eli L. Diamond, Keren B. Sturtz, Gang Feng, Stefanie K. Drescher, Micaela B. Reddy, Bhaswati Sengupta, Arnab K. Maity, Suzy A. Brown, Anurag Singh, Eric N. Brown, Brian R. Baer, Jim Wong, Tung-Chung Mou, Wen-I Wu, Dean R. Kahn, Sunyana Gadal, Neal Rosen, John J. Gaudino, Patrice A. Lee, Dylan P. Hartley, S. Michael. Rothenberg","doi":"10.1158/2159-8290.cd-24-0024","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0024","url":null,"abstract":"RAF inhibitors have transformed treatment for BRAF V600-mutant cancer patients, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAF V600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling. PF-07799933 ± binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAF V600E with acquired resistance to current RAF inhibitors. We treated patients with treatment-refractory BRAF-mutant solid tumors in a first-in-human clinical trial (NCT05355701) that utilized a novel, flexible, pharmacokinetics-informed dose escalation design that allowed rapid achievement of PF-07799933 efficacious concentrations. PF-07799933 ± binimetinib was well-tolerated and resulted in multiple confirmed responses, systemically and in the brain, in BRAF-mutant cancer patients refractory to approved RAF inhibitors.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":28.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140819330","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 : 2024-05-01DOI: 10.1158/2159-8290.CD-22-0952
Andrew J Dunbar, Robert L Bowman, Young C Park, Kavi O'Connor, Franco Izzo, Robert M Myers, Abdul Karzai, Zachary Zaroogian, Won Jun Kim, Inés Fernández-Maestre, Michael R Waarts, Abbas Nazir, Wenbin Xiao, Tamara Codilupi, Max Brodsky, Mirko Farina, Louise Cai, Sheng F Cai, Benjamin Wang, Wenbin An, Julie L Yang, Shoron Mowla, Shira E Eisman, Amritha Varshini Hanasoge Somasundara, Jacob L Glass, Tanmay Mishra, Remie Houston, Emily Guzzardi, Anthony R Martinez Benitez, Aaron D Viny, Richard P Koche, Sara C Meyer, Dan A Landau, Ross L Levine
Gain-of-function mutations activating JAK/STAT signaling are seen in the majority of patients with myeloproliferative neoplasms (MPN), most commonly JAK2V617F. Although clinically approved JAK inhibitors improve symptoms and outcomes in MPNs, remissions are rare, and mutant allele burden does not substantively change with chronic therapy. We hypothesized this is due to limitations of current JAK inhibitors to potently and specifically abrogate mutant JAK2 signaling. We therefore developed a conditionally inducible mouse model allowing for sequential activation, and then inactivation, of Jak2V617F from its endogenous locus using a combined Dre-rox/Cre-lox dual-recombinase system. Jak2V617F deletion abrogates MPN features, induces depletion of mutant-specific hematopoietic stem/progenitor cells, and extends overall survival to an extent not observed with pharmacologic JAK inhibition, including when cooccurring with somatic Tet2 loss. Our data suggest JAK2V617F represents the best therapeutic target in MPNs and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependencies in vivo.
Significance: Current JAK inhibitors to treat myeloproliferative neoplasms are ineffective at eradicating mutant cells. We developed an endogenously expressed Jak2V617F dual-recombinase knock-in/knock-out model to investigate Jak2V617F oncogenic reversion in vivo. Jak2V617F deletion abrogates MPN features and depletes disease-sustaining MPN stem cells, suggesting improved Jak2V617F targeting offers the potential for greater therapeutic efficacy. See related commentary by Celik and Challen, p. 701. This article is featured in Selected Articles from This Issue, p. 695.
大多数骨髓增生性肿瘤(MPN)患者都存在激活 JAK/STAT 信号转导的功能增益突变,其中最常见的是 JAK2V617F。虽然临床批准的 JAK 抑制剂能改善骨髓增生性肿瘤的症状和预后,但缓解的情况很少见,突变等位基因的负担也不会随着长期治疗而发生实质性改变。我们推测这是由于目前的 JAK 抑制剂在有效和特异性地消减突变 JAK2 信号传导方面存在局限性。因此,我们开发了一种条件诱导型小鼠模型,利用 Dre-rox/Cre-lox 组合双重组酶系统从内源性基因座依次激活和灭活 Jak2V617F。Jak2V617F缺失可消除MPN特征,诱导突变特异性造血干细胞/祖细胞的耗竭,并延长总生存期,其延长程度是药物性JAK抑制所无法观察到的,包括与体细胞Tet2缺失同时发生时。我们的数据表明,JAK2V617F是多发性骨髓瘤的最佳治疗靶点,并证明了双重组蛋白酶系统对评估体内突变特异性致癌依赖性的治疗意义。
{"title":"Jak2V617F Reversible Activation Shows Its Essential Requirement in Myeloproliferative Neoplasms.","authors":"Andrew J Dunbar, Robert L Bowman, Young C Park, Kavi O'Connor, Franco Izzo, Robert M Myers, Abdul Karzai, Zachary Zaroogian, Won Jun Kim, Inés Fernández-Maestre, Michael R Waarts, Abbas Nazir, Wenbin Xiao, Tamara Codilupi, Max Brodsky, Mirko Farina, Louise Cai, Sheng F Cai, Benjamin Wang, Wenbin An, Julie L Yang, Shoron Mowla, Shira E Eisman, Amritha Varshini Hanasoge Somasundara, Jacob L Glass, Tanmay Mishra, Remie Houston, Emily Guzzardi, Anthony R Martinez Benitez, Aaron D Viny, Richard P Koche, Sara C Meyer, Dan A Landau, Ross L Levine","doi":"10.1158/2159-8290.CD-22-0952","DOIUrl":"10.1158/2159-8290.CD-22-0952","url":null,"abstract":"<p><p>Gain-of-function mutations activating JAK/STAT signaling are seen in the majority of patients with myeloproliferative neoplasms (MPN), most commonly JAK2V617F. Although clinically approved JAK inhibitors improve symptoms and outcomes in MPNs, remissions are rare, and mutant allele burden does not substantively change with chronic therapy. We hypothesized this is due to limitations of current JAK inhibitors to potently and specifically abrogate mutant JAK2 signaling. We therefore developed a conditionally inducible mouse model allowing for sequential activation, and then inactivation, of Jak2V617F from its endogenous locus using a combined Dre-rox/Cre-lox dual-recombinase system. Jak2V617F deletion abrogates MPN features, induces depletion of mutant-specific hematopoietic stem/progenitor cells, and extends overall survival to an extent not observed with pharmacologic JAK inhibition, including when cooccurring with somatic Tet2 loss. Our data suggest JAK2V617F represents the best therapeutic target in MPNs and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependencies in vivo.</p><p><strong>Significance: </strong>Current JAK inhibitors to treat myeloproliferative neoplasms are ineffective at eradicating mutant cells. We developed an endogenously expressed Jak2V617F dual-recombinase knock-in/knock-out model to investigate Jak2V617F oncogenic reversion in vivo. Jak2V617F deletion abrogates MPN features and depletes disease-sustaining MPN stem cells, suggesting improved Jak2V617F targeting offers the potential for greater therapeutic efficacy. See related commentary by Celik and Challen, p. 701. This article is featured in Selected Articles from This Issue, p. 695.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":28.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11061606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139478024","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 : 2024-05-01DOI: 10.1158/2159-8290.CD-23-1161
Dalia Rosano, Emre Sofyali, Heena Dhiman, Chiara Ghirardi, Diana Ivanoiu, Timon Heide, Andrea Vingiani, Alessia Bertolotti, Giancarlo Pruneri, Eleonora Canale, Hannah F Dewhurst, Debjani Saha, Neil Slaven, Iros Barozzi, Tong Li, Grigory Zemlyanskiy, Henry Phillips, Chela James, Balázs Győrffy, Claire Lynn, George D Cresswell, Farah Rehman, Roberta Noberini, Tiziana Bonaldi, Andrea Sottoriva, Luca Magnani
Patients with estrogen receptor-positive breast cancer receive adjuvant endocrine therapies (ET) that delay relapse by targeting clinically undetectable micrometastatic deposits. Yet, up to 50% of patients relapse even decades after surgery through unknown mechanisms likely involving dormancy. To investigate genetic and transcriptional changes underlying tumor awakening, we analyzed late relapse patients and longitudinally profiled a rare cohort treated with long-term neoadjuvant ETs until progression. Next, we developed an in vitro evolutionary study to record the adaptive strategies of individual lineages in unperturbed parallel experiments. Our data demonstrate that ETs induce nongenetic cell state transitions into dormancy in a stochastic subset of cells via epigenetic reprogramming. Single lineages with divergent phenotypes awaken unpredictably in the absence of recurrent genetic alterations. Targeting the dormant epigenome shows promising activity against adapting cancer cells. Overall, this study uncovers the contribution of epigenetic adaptation to the evolution of resistance to ETs.
Significance: This study advances the understanding of therapy-induced dormancy with potential clinical implications for breast cancer. Estrogen receptor-positive breast cancer cells adapt to endocrine treatment by entering a dormant state characterized by strong heterochromatinization with no recurrent genetic changes. Targeting the epigenetic rewiring impairs the adaptation of cancer cells to ETs. See related commentary by Llinas-Bertran et al., p. 704. This article is featured in Selected Articles from This Issue, p. 695.
雌激素受体阳性乳腺癌患者接受辅助内分泌疗法(ET)后,可通过针对临床上检测不到的微转移沉积物来延缓复发。然而,即使在术后数十年,仍有高达50%的患者会复发,其原因不明,可能涉及休眠机制。为了研究肿瘤苏醒背后的基因和转录变化,我们对晚期复发患者进行了分析,并纵向分析了长期接受新辅助 ET 治疗直至病情进展的罕见人群。接下来,我们开展了一项体外进化研究,在不受干扰的平行实验中记录单个品系的适应策略。我们的数据证明,ET 通过表观遗传重编程诱导随机亚群细胞的非遗传细胞状态转变为休眠状态。在没有经常性基因改变的情况下,具有不同表型的单系会不可预测地苏醒。以休眠表观基因组为靶点,对适应性癌细胞具有良好的活性。总之,这项研究揭示了表观遗传适应对ETs耐药性进化的贡献:这项研究加深了人们对治疗诱导休眠的理解,对乳腺癌具有潜在的临床意义。雌激素受体阳性乳腺癌细胞通过进入休眠状态来适应内分泌治疗,这种休眠状态的特点是强异染色质化,没有复发性遗传变化。靶向表观遗传学改组会损害癌细胞对 ET 的适应。
{"title":"Long-term Multimodal Recording Reveals Epigenetic Adaptation Routes in Dormant Breast Cancer Cells.","authors":"Dalia Rosano, Emre Sofyali, Heena Dhiman, Chiara Ghirardi, Diana Ivanoiu, Timon Heide, Andrea Vingiani, Alessia Bertolotti, Giancarlo Pruneri, Eleonora Canale, Hannah F Dewhurst, Debjani Saha, Neil Slaven, Iros Barozzi, Tong Li, Grigory Zemlyanskiy, Henry Phillips, Chela James, Balázs Győrffy, Claire Lynn, George D Cresswell, Farah Rehman, Roberta Noberini, Tiziana Bonaldi, Andrea Sottoriva, Luca Magnani","doi":"10.1158/2159-8290.CD-23-1161","DOIUrl":"10.1158/2159-8290.CD-23-1161","url":null,"abstract":"<p><p>Patients with estrogen receptor-positive breast cancer receive adjuvant endocrine therapies (ET) that delay relapse by targeting clinically undetectable micrometastatic deposits. Yet, up to 50% of patients relapse even decades after surgery through unknown mechanisms likely involving dormancy. To investigate genetic and transcriptional changes underlying tumor awakening, we analyzed late relapse patients and longitudinally profiled a rare cohort treated with long-term neoadjuvant ETs until progression. Next, we developed an in vitro evolutionary study to record the adaptive strategies of individual lineages in unperturbed parallel experiments. Our data demonstrate that ETs induce nongenetic cell state transitions into dormancy in a stochastic subset of cells via epigenetic reprogramming. Single lineages with divergent phenotypes awaken unpredictably in the absence of recurrent genetic alterations. Targeting the dormant epigenome shows promising activity against adapting cancer cells. Overall, this study uncovers the contribution of epigenetic adaptation to the evolution of resistance to ETs.</p><p><strong>Significance: </strong>This study advances the understanding of therapy-induced dormancy with potential clinical implications for breast cancer. Estrogen receptor-positive breast cancer cells adapt to endocrine treatment by entering a dormant state characterized by strong heterochromatinization with no recurrent genetic changes. Targeting the epigenetic rewiring impairs the adaptation of cancer cells to ETs. See related commentary by Llinas-Bertran et al., p. 704. This article is featured in Selected Articles from This Issue, p. 695.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":28.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11061610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140286995","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 : 2024-05-01DOI: 10.1158/2159-8290.CD-24-0248
{"title":"Correction: Highlights of FDA Oncology Approvals in 2023: Bispecific T-cell Engagers, Pediatric Indications, and Inclusive Drug Development.","authors":"","doi":"10.1158/2159-8290.CD-24-0248","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0248","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":28.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140848145","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 : 2024-05-01DOI: 10.1158/2159-8290.CD-23-0656
Shreoshi Pal Choudhuri, Luc Girard, Jun Yi Stanley Lim, Jillian F Wise, Braeden Freitas, Di Yang, Edmond Wong, Seth Hamilton, Victor D Chien, Yoon Jung Kim, Collin Gilbreath, Jun Zhong, Sarah Phat, David T Myers, Camilla L Christensen, Hanieh Mazloom-Farsibaf, Marcello Stanzione, Kwok-Kin Wong, Yin P Hung, Anna F Farago, Catherine B Meador, Nicholas J Dyson, Michael S Lawrence, Sihan Wu, Benjamin J Drapkin
Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here, we present a preclinical system that recapitulates acquired cross-resistance, developed from 51 patient-derived xenograft (PDX) models. Each model was tested in vivo against three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. These drug-response profiles captured hallmark clinical features of SCLC, such as the emergence of treatment-refractory disease after early relapse. For one patient, serial PDX models revealed that cross-resistance was acquired through MYC amplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that MYC paralog amplifications on ecDNAs were recurrent in relapsed cross-resistant SCLC, and this was corroborated in tumor biopsies from relapsed patients. We conclude that ecDNAs with MYC paralogs are recurrent drivers of cross-resistance in SCLC.
Significance: SCLC is initially chemosensitive, but acquired cross-resistance renders this disease refractory to further treatment and ultimately fatal. The genomic drivers of this transformation are unknown. We use a population of PDX models to discover that amplifications of MYC paralogs on ecDNA are recurrent drivers of acquired cross-resistance in SCLC. This article is featured in Selected Articles from This Issue, p. 695.
{"title":"Acquired Cross-Resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of MYC Paralogs.","authors":"Shreoshi Pal Choudhuri, Luc Girard, Jun Yi Stanley Lim, Jillian F Wise, Braeden Freitas, Di Yang, Edmond Wong, Seth Hamilton, Victor D Chien, Yoon Jung Kim, Collin Gilbreath, Jun Zhong, Sarah Phat, David T Myers, Camilla L Christensen, Hanieh Mazloom-Farsibaf, Marcello Stanzione, Kwok-Kin Wong, Yin P Hung, Anna F Farago, Catherine B Meador, Nicholas J Dyson, Michael S Lawrence, Sihan Wu, Benjamin J Drapkin","doi":"10.1158/2159-8290.CD-23-0656","DOIUrl":"10.1158/2159-8290.CD-23-0656","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here, we present a preclinical system that recapitulates acquired cross-resistance, developed from 51 patient-derived xenograft (PDX) models. Each model was tested in vivo against three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. These drug-response profiles captured hallmark clinical features of SCLC, such as the emergence of treatment-refractory disease after early relapse. For one patient, serial PDX models revealed that cross-resistance was acquired through MYC amplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that MYC paralog amplifications on ecDNAs were recurrent in relapsed cross-resistant SCLC, and this was corroborated in tumor biopsies from relapsed patients. We conclude that ecDNAs with MYC paralogs are recurrent drivers of cross-resistance in SCLC.</p><p><strong>Significance: </strong>SCLC is initially chemosensitive, but acquired cross-resistance renders this disease refractory to further treatment and ultimately fatal. The genomic drivers of this transformation are unknown. We use a population of PDX models to discover that amplifications of MYC paralogs on ecDNA are recurrent drivers of acquired cross-resistance in SCLC. This article is featured in Selected Articles from This Issue, p. 695.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":28.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11061613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139930162","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 : 2024-05-01DOI: 10.1158/2159-8290.CD-23-0857
Minae An, Arnav Mehta, Byung Hoon Min, You Jeong Heo, Samuel J Wright, Milan Parikh, Lynn Bi, Hyuk Lee, Tae Jun Kim, Song-Yi Lee, Jeonghyeon Moon, Ryan J Park, Matthew R Strickland, Woong-Yang Park, Won Ki Kang, Kyoung-Mee Kim, Seung Tae Kim, Samuel J Klempner, Jeeyun Lee
Adding anti-programmed cell death protein 1 (anti-PD-1) to 5-fluorouracil (5-FU)/platinum improves survival in some advanced gastroesophageal adenocarcinomas (GEA). To understand the effects of chemotherapy and immunotherapy, we conducted a phase II first-line trial (n = 47) sequentially adding pembrolizumab to 5-FU/platinum in advanced GEA. Using serial biopsy of the primary tumor at baseline, after one cycle of 5-FU/platinum, and after the addition of pembrolizumab, we transcriptionally profiled 358,067 single cells to identify evolving multicellular tumor microenvironment (TME) networks. Chemotherapy induced early on-treatment multicellular hubs with tumor-reactive T-cell and M1-like macrophage interactions in slow progressors. Faster progression featured increased MUC5A and MSLN containing treatment resistance programs in tumor cells and M2-like macrophages with immunosuppressive stromal interactions. After pembrolizumab, we observed increased CD8 T-cell infiltration and development of an immunity hub involving tumor-reactive CXCL13 T-cell program and epithelial interferon-stimulated gene programs. Strategies to drive increases in antitumor immune hub formation could expand the portion of patients benefiting from anti-PD-1 approaches.
Significance: The benefit of 5-FU/platinum with anti-PD-1 in first-line advanced gastric cancer is limited to patient subgroups. Using a trial with sequential anti-PD-1, we show coordinated induction of multicellular TME hubs informs the ability of anti-PD-1 to potentiate T cell-driven responses. Differential TME hub development highlights features that underlie clinical outcomes. This article is featured in Selected Articles from This Issue, p. 695.
在5-FU/铂中加入抗PD1可提高一些晚期胃食管腺癌(GEA)的生存率。为了了解化疗和免疫疗法的效果,我们开展了一项II期前线试验(n = 47),在晚期胃食管腺癌的5-FU/铂中依次加入pembrolizumab。通过在基线、5-FU/铂治疗一个周期后以及添加 pembrolizumab 后对原发肿瘤进行连续活检,我们对 358,067 个单细胞进行了转录分析,以确定不断演变的多细胞 TME 网络。化疗诱导了治疗早期的多细胞中心,在进展缓慢的患者中,肿瘤反应性T细胞和M1样巨噬细胞相互作用。进展较快者的特点是肿瘤细胞中含有抗药性程序的MUC5A和MSLN以及具有免疫抑制基质相互作用的M2样巨噬细胞增多。使用 pembrolizumab 后,我们观察到 CD8 T 细胞浸润增加,免疫中枢发展,其中包括肿瘤反应性 CXCL13 T 细胞程序和上皮干扰素刺激基因程序。推动抗肿瘤免疫中枢形成的策略可以扩大从抗PD1方法中获益的患者比例。
{"title":"Early Immune Remodeling Steers Clinical Response to First-Line Chemoimmunotherapy in Advanced Gastric Cancer.","authors":"Minae An, Arnav Mehta, Byung Hoon Min, You Jeong Heo, Samuel J Wright, Milan Parikh, Lynn Bi, Hyuk Lee, Tae Jun Kim, Song-Yi Lee, Jeonghyeon Moon, Ryan J Park, Matthew R Strickland, Woong-Yang Park, Won Ki Kang, Kyoung-Mee Kim, Seung Tae Kim, Samuel J Klempner, Jeeyun Lee","doi":"10.1158/2159-8290.CD-23-0857","DOIUrl":"10.1158/2159-8290.CD-23-0857","url":null,"abstract":"<p><p>Adding anti-programmed cell death protein 1 (anti-PD-1) to 5-fluorouracil (5-FU)/platinum improves survival in some advanced gastroesophageal adenocarcinomas (GEA). To understand the effects of chemotherapy and immunotherapy, we conducted a phase II first-line trial (n = 47) sequentially adding pembrolizumab to 5-FU/platinum in advanced GEA. Using serial biopsy of the primary tumor at baseline, after one cycle of 5-FU/platinum, and after the addition of pembrolizumab, we transcriptionally profiled 358,067 single cells to identify evolving multicellular tumor microenvironment (TME) networks. Chemotherapy induced early on-treatment multicellular hubs with tumor-reactive T-cell and M1-like macrophage interactions in slow progressors. Faster progression featured increased MUC5A and MSLN containing treatment resistance programs in tumor cells and M2-like macrophages with immunosuppressive stromal interactions. After pembrolizumab, we observed increased CD8 T-cell infiltration and development of an immunity hub involving tumor-reactive CXCL13 T-cell program and epithelial interferon-stimulated gene programs. Strategies to drive increases in antitumor immune hub formation could expand the portion of patients benefiting from anti-PD-1 approaches.</p><p><strong>Significance: </strong>The benefit of 5-FU/platinum with anti-PD-1 in first-line advanced gastric cancer is limited to patient subgroups. Using a trial with sequential anti-PD-1, we show coordinated induction of multicellular TME hubs informs the ability of anti-PD-1 to potentiate T cell-driven responses. Differential TME hub development highlights features that underlie clinical outcomes. This article is featured in Selected Articles from This Issue, p. 695.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":28.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11061611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139691220","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}