Abstract 604: Targeting casein kinase 1 alpha (CK1 alpha) and transcriptional CDKs (CDK7/9) in human liposarcomas
Abstract Introduction: Liposarcomas (LPS) are rare mesenchymal cell malignancies of adipocytic origin that are diagnosed in more than 3500 patients in the US each year. The two most common subtypes, well-differentiated LPS (WDLPS) and dedifferentiated LPS (DDLPS), are characterized by extrachromosom...
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| Published in: | Cancer research (Chicago, Ill.) Vol. 84; no. 6_Supplement; p. 604 |
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| Main Authors: | , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
22-03-2024
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| Online Access: | Get full text |
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| Summary: | Abstract
Introduction: Liposarcomas (LPS) are rare mesenchymal cell malignancies of adipocytic origin that are diagnosed in more than 3500 patients in the US each year. The two most common subtypes, well-differentiated LPS (WDLPS) and dedifferentiated LPS (DDLPS), are characterized by extrachromosomal DNA amplifications harboring the MDM2 (100%) and CDK4 (90+%) genes, generally with wild type TP53. Management of metastatic or surgically unresectable LPS remains purely palliative. Recent clinical trials targeting MDM2 or CDK4/6 with small-molecule inhibitors have shown promise but have been hampered by dose-limiting toxicities. The development of new therapeutics is greatly needed to improve outcomes for patients with LPS.
Results: To identify unique liposarcoma-specific vulnerabilities, we screened multiple human LPS cell lines for transcriptional CDK expression and found high levels of CDK7 and CDK9. We demonstrate that CDK9 inhibitors suppress LPS cell growth and induce apoptosis by decreasing MDM2 levels while inducing expression of p53. To enhance p53 activation in these cells, we screened for expression of known regulators of p53, including CK1α, whose inhibition has previously been shown to activate p53. We demonstrate that LPS cells express CK1α and that the cytotoxic effects of CDK9 inhibitors are enhanced upon CK1α depletion. These data led us to examine combined targeting of CK1α and CDK9 in LPS with the novel agent BTX-A51, which has previously been shown to inhibit CK1α, CDK9, as well as CDK7 with nanomolar efficacy in AML models. BTX-A51 potently reduces expression of MDM2 with marked induction of p53, resulting in profound apoptosis of LPS cells. Through CRISPR/Cas9-mediated p53 knockout, we establish that BTX-A51-mediated apoptosis is primarily p53-dependent. However, BTX-A51 also reduces expression of MCL1 and primes LPS cell lines and primary LPS cells for BIM-induced apoptosis, as demonstrated by BH3 profiling. Importantly, preliminary in vivo data in an LPS patient-derived xenograft model reveal that BTX-A51 is well-tolerated with tumor growth inhibition.
Conclusions: Our results suggest that BTX-A51 has potent preclinical efficacy in treating LPS, primarily through inhibition of CK1α and CDK9. Future mechanistic studies will further clarify mechanisms of BTX-A51-mediated apoptosis, as well as the contribution of CDK7 inhibition to anti-tumor activity. Our data justify a planned clinical trial that will evaluate the efficacy of BTX-A51 in patients with advanced WDLPS or DDLPS.
Citation Format: Renyan Liu, Nicole L. Solimini, Patrick Bhola, Timothy B. Branigan, Jie Hao, Xin Wang, Roshen Alharthi, Michael Yorsz, Shaili Soni, Cing-siang Hu, Irit Snir-Alkalay, Prafulla Gokhale, Anthony Letai, Yinon Yinon Ben-Neriah, George D. Demetri, Geoffrey I. Shapiro. Targeting casein kinase 1 alpha (CK1 alpha) and transcriptional CDKs (CDK7/9) in human liposarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 604. |
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| ISSN: | 1538-7445 1538-7445 |
| DOI: | 10.1158/1538-7445.AM2024-604 |