Novel covalent CDK7 inhibitor potently induces apoptosis in acute myeloid leukemia and synergizes with Venetoclax

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• dc.contributor.author Gaur, Tarang
• dc.contributor.author Poddutoori, Ramulu
• dc.contributor.author Khare, Leena
• dc.contributor.author Bagal, Bhausaheb
• dc.contributor.author Rashmi, Sonal
• dc.contributor.author Patkar, Nikhil
• dc.contributor.author Tembhare, Prashant
• dc.contributor.author Pg, Subramanian
• dc.contributor.author Shetty, Dhanlaxmi
• dc.contributor.author Dutt, Amit
• dc.contributor.author Zhang, Qi
• dc.contributor.author Konopleva, Marina
• dc.contributor.author Platzbeckar, Uwe
• dc.contributor.author Gupta, Sudeep
• dc.contributor.author Samajdar, Susanta
• dc.contributor.author Ramchandra, Murali
• dc.contributor.author Khattry, Navin
• dc.contributor.author Hasan, Syed K.
• dc.date.accessioned 2023-10-30T07:08:05Z
• dc.date.available 2023-10-30T07:08:05Z
• dc.date.issued 2023
• dc.description.abstract Introduction: The emergence of resistance to the highly successful BCL2-directed therapy is a major unmet need in acute myeloid leukemia (AML), an aggressive malignancy with poor survival rates. Towards identifying therapeutic options for AML patients who progress on BCL2-directed therapy, we studied a clinical-stage CDK7 inhibitor XL102, which is being evaluated in solid tumors (NCT04726332). Materials and methods: To determine the anti-proliferative effects of XL102, we performed experiments including time-resolved fluorescence resonance energy transfer, target occupancy, cell cycle and apoptosis-based assays. We also included genetically characterized primary myeloid blasts from de novo and relapsed/refractory AML patients. For mechanistic studies, CRISPR/Cas9 mediated knockout of CDK7 and c-Myc and immunoblotting were performed. NOD/SCID orthotropic and subcutaneous AML xenografts were used to determine anti-leukemic effects. To assess the synergistic effects of XL102 with Venetoclax, we performed RNA sequencing and gene set enrichment analysis using Venetoclax sensitive and resistant model systems. Results: XL102, a highly specific, orally bioavailable covalent inhibitor of CDK7. Inhibitory effect on CDK7 by XL102 in primary myeloid blasts (n = 54) was in nanomolar range (mean = 300 nM; range = 4.0-952 nM). XL102 treated AML cells showed a reduction in phosphorylation levels of Serine 2/5/7 at carboxy-terminal domain of RNA polymerase II. T-loop phosphorylation of CDK1(Thr161) and CDK2(Thr160) was inhibited by XL102 in dose-dependent manner leading to cell-cycle arrest. c-Myc downregulation and enhanced levels of p53 and p21 in XL102 treated cells were observed. Increased levels of p21 and activation of p53 by XL102 were mimicked by genetic ablation of CDK7, which supports that the observed effects of XL102 are due to CDK7 inhibition. XL102 treated AML xenografts showed remarkable reduction in hCD45 + marrow cells (mean = 0.60%; range = 0.04%-3.53%) compared to vehicle control (mean = 38.2%; range = 10.1%-78%), with corresponding increase in p53, p21 and decrease in c-Myc levels. The data suggests XL102 induces apoptosis in AML cells via CDK7/c-Myc/p53 axis. RNA-sequencing from paired Venetoclax-sensitive and Venetoclax-resistant cells treated with XL102 showed downregulation of genes involved in proliferation and apoptosis. Conclusion: Taken together, XL102 with Venetoclax led to synergistic effects in overcoming resistance and provided a strong rationale for clinical evaluation of XL102 as a single agent and in combination with Venetoclax.
• dc.format.mimetype application/pdf
• dc.identifier.citation Gaur T, Poddutoori R, Khare L, Bagal B, Rashmi S, Patkar N, Tembhare P, Pg S, Shetty D, Dutt A, Zhang Q, Konopleva M, Platzbeckar U, Gupta S, Samajdar S, Ramchandra M, Khattry N, Hasan SK. Novel covalent CDK7 inhibitor potently induces apoptosis in acute myeloid leukemia and synergizes with Venetoclax. J Exp Clin Cancer Res. 2023 Jul 29;42(1):186. DOI: 10.1186/s13046-023-02750-w
• dc.identifier.doi http://dx.doi.org/10.1186/s13046-023-02750-w
• dc.identifier.issn 0392-9078
• dc.identifier.uri http://hdl.handle.net/10230/58182
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof J Exp Clin Cancer Res. 2023 Jul 29;42(1):186
• dc.rights © The Author(s) 2023.Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Acute myeloid leukemia
• dc.subject.keyword Apoptosis
• dc.subject.keyword CDK7 inhibition
• dc.subject.keyword CRISPR/Cas9
• dc.subject.keyword Cell cycle
• dc.subject.keyword Venetoclax resistance
• dc.subject.keyword Xenografts
• dc.title Novel covalent CDK7 inhibitor potently induces apoptosis in acute myeloid leukemia and synergizes with Venetoclax
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion