A. Shastri, S. Chakraborty, C. Morganti, H. Zhang, B. Rivera-Pena, K. Ito, M. Konopleva
{"title":"一种Stat3降解剂显示出对耐药MDS和AML的临床前疗效","authors":"A. Shastri, S. Chakraborty, C. Morganti, H. Zhang, B. Rivera-Pena, K. Ito, M. Konopleva","doi":"10.1016/j.lrr.2024.100445","DOIUrl":null,"url":null,"abstract":"<div><h3>Introduction</h3><p>High-risk MDS & AML are the result of malignant transformation of an immature hematopoietic precursor. Venetoclax (Ven) is a selective inhibitor of the anti-apoptotic BCL2 protein that is FDA approved for the treatment of AML, despite which, the overall cure rates in HR-MDS and AML are dismal. Signal transducer and activator of transcription 3 (STAT3) is de-methylation and overexpression in MDS & AML stem cells. It is associated with an adverse prognosis in a large cohort of patients. We have also demonstrated that STAT3 controls several important leukemic drivers such as the anti-apoptotic protein MCL1, which is the central mechanism of venetoclax resistance.</p></div><div><h3>Methods</h3><p>Ven resistant AML cell lines (MOLM-13, MV-4-11) demonstrated an increased expression of STAT3/ Phospho-STAT3 and the down-stream effector MCL1 when compared to parental cell lines. Data from > 90 AML patients treated with prior venetoclax show that high expression of STAT3 correlated with worse overall survival and remission duration.</p></div><div><h3>Results</h3><p>A clinical degrader of STAT3 resulted in degradation of STAT3 in both parental and ven resistant cancer cell lines. STAT3 degradation also resulted in increased apoptosis in parental & Ven resistant MOLM-13 cell line. In primary patient colony assays, there was increased erythroid and myeloid differentiation on treatment with a STAT3 degrader. Furthermore, murine model of venetoclax resistance showed significant reduction in STAT3 & MCL1 on treatment with the STAT3 degrader.</p></div><div><h3>Conclusions</h3><p>Targeting STAT3 and downstream MCL1 is novel strategy in MDS/AML that can spur clinical development of the STAT3 degraders especially given the significant side profile of direct MCL1 inhibitors.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":"21 ","pages":"Article 100445"},"PeriodicalIF":0.7000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048924000359/pdfft?md5=34565d0330b117d488c84b68d03049c3&pid=1-s2.0-S2213048924000359-main.pdf","citationCount":"0","resultStr":"{\"title\":\"A STAT3 DEGRADER DEMONSTRATES PRE-CLINICAL EFFICACY IN VENETOCLAX RESISTANT MDS & AML\",\"authors\":\"A. Shastri, S. Chakraborty, C. Morganti, H. Zhang, B. Rivera-Pena, K. Ito, M. Konopleva\",\"doi\":\"10.1016/j.lrr.2024.100445\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Introduction</h3><p>High-risk MDS & AML are the result of malignant transformation of an immature hematopoietic precursor. Venetoclax (Ven) is a selective inhibitor of the anti-apoptotic BCL2 protein that is FDA approved for the treatment of AML, despite which, the overall cure rates in HR-MDS and AML are dismal. Signal transducer and activator of transcription 3 (STAT3) is de-methylation and overexpression in MDS & AML stem cells. It is associated with an adverse prognosis in a large cohort of patients. We have also demonstrated that STAT3 controls several important leukemic drivers such as the anti-apoptotic protein MCL1, which is the central mechanism of venetoclax resistance.</p></div><div><h3>Methods</h3><p>Ven resistant AML cell lines (MOLM-13, MV-4-11) demonstrated an increased expression of STAT3/ Phospho-STAT3 and the down-stream effector MCL1 when compared to parental cell lines. Data from > 90 AML patients treated with prior venetoclax show that high expression of STAT3 correlated with worse overall survival and remission duration.</p></div><div><h3>Results</h3><p>A clinical degrader of STAT3 resulted in degradation of STAT3 in both parental and ven resistant cancer cell lines. STAT3 degradation also resulted in increased apoptosis in parental & Ven resistant MOLM-13 cell line. In primary patient colony assays, there was increased erythroid and myeloid differentiation on treatment with a STAT3 degrader. Furthermore, murine model of venetoclax resistance showed significant reduction in STAT3 & MCL1 on treatment with the STAT3 degrader.</p></div><div><h3>Conclusions</h3><p>Targeting STAT3 and downstream MCL1 is novel strategy in MDS/AML that can spur clinical development of the STAT3 degraders especially given the significant side profile of direct MCL1 inhibitors.</p></div>\",\"PeriodicalId\":38435,\"journal\":{\"name\":\"Leukemia Research Reports\",\"volume\":\"21 \",\"pages\":\"Article 100445\"},\"PeriodicalIF\":0.7000,\"publicationDate\":\"2024-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S2213048924000359/pdfft?md5=34565d0330b117d488c84b68d03049c3&pid=1-s2.0-S2213048924000359-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Leukemia Research Reports\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2213048924000359\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Leukemia Research Reports","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2213048924000359","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"HEMATOLOGY","Score":null,"Total":0}
A STAT3 DEGRADER DEMONSTRATES PRE-CLINICAL EFFICACY IN VENETOCLAX RESISTANT MDS & AML
Introduction
High-risk MDS & AML are the result of malignant transformation of an immature hematopoietic precursor. Venetoclax (Ven) is a selective inhibitor of the anti-apoptotic BCL2 protein that is FDA approved for the treatment of AML, despite which, the overall cure rates in HR-MDS and AML are dismal. Signal transducer and activator of transcription 3 (STAT3) is de-methylation and overexpression in MDS & AML stem cells. It is associated with an adverse prognosis in a large cohort of patients. We have also demonstrated that STAT3 controls several important leukemic drivers such as the anti-apoptotic protein MCL1, which is the central mechanism of venetoclax resistance.
Methods
Ven resistant AML cell lines (MOLM-13, MV-4-11) demonstrated an increased expression of STAT3/ Phospho-STAT3 and the down-stream effector MCL1 when compared to parental cell lines. Data from > 90 AML patients treated with prior venetoclax show that high expression of STAT3 correlated with worse overall survival and remission duration.
Results
A clinical degrader of STAT3 resulted in degradation of STAT3 in both parental and ven resistant cancer cell lines. STAT3 degradation also resulted in increased apoptosis in parental & Ven resistant MOLM-13 cell line. In primary patient colony assays, there was increased erythroid and myeloid differentiation on treatment with a STAT3 degrader. Furthermore, murine model of venetoclax resistance showed significant reduction in STAT3 & MCL1 on treatment with the STAT3 degrader.
Conclusions
Targeting STAT3 and downstream MCL1 is novel strategy in MDS/AML that can spur clinical development of the STAT3 degraders especially given the significant side profile of direct MCL1 inhibitors.