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Preclinical Modeling of Leiomyosarcoma Identifies Susceptibility to Transcriptional CDK Inhibitors through Antagonism of E2F-Driven Oncogenic Gene Expression.

Authors
  • Hemming, Matthew L1
  • Bhola, Patrick1
  • Loycano, Michael A2
  • Anderson, Justin A2
  • Taddei, Madeleine L2
  • Doyle, Leona A3
  • Lavrova, Elizaveta1
  • Andersen, Jessica L1
  • Klega, Kelly S4
  • Benson, Morgan R4
  • Crompton, Brian D4
  • Raut, Chandrajit P5
  • George, Suzanne1
  • Letai, Anthony1
  • Demetri, George D1, 6
  • Sicinska, Ewa2
  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • 2 Department of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • 3 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
  • 4 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • 5 Department of Surgery, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • 6 Ludwig Center at Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
Type
Published Article
Journal
Clinical Cancer Research
Publisher
American Association for Cancer Research
Publication Date
Jun 01, 2022
Volume
28
Issue
11
Pages
2397–2408
Identifiers
DOI: 10.1158/1078-0432.CCR-21-3523
PMID: 35325095
Source
Medline
Language
English
License
Unknown

Abstract

Leiomyosarcoma (LMS) is a neoplasm characterized by smooth muscle differentiation, complex copy-number alterations, tumor suppressor loss, and the absence of recurrent driver mutations. Clinical management for advanced disease relies on the use of empiric cytotoxic chemotherapy with limited activity, and novel targeted therapies supported by preclinical research on LMS biology are urgently needed. A lack of fidelity of established LMS cell lines to their mesenchymal neoplasm of origin has limited translational understanding of this disease, and few other preclinical models have been established. Here, we characterize patient-derived xenograft (PDX) models of LMS, assessing fidelity to their tumors of origin and performing preclinical evaluation of candidate therapies. We implanted 49 LMS surgical samples into immunocompromised mice. Engrafting tumors were characterized by histology, targeted next-generation sequencing, RNA sequencing, and ultra-low passage whole-genome sequencing. Candidate therapies were selected based on prior evidence of pathway activation or high-throughput dynamic BH3 profiling. We show that LMS PDX maintain the histologic appearance, copy-number alterations, and transcriptional program of their parental tumors across multiple xenograft passages. Transcriptionally, LMS PDX cocluster with paired LMS patient-derived samples and differ primarily in host-related immunologic and microenvironment signatures. We identify susceptibility of LMS PDX to transcriptional cyclin-dependent kinase (CDK) inhibition, which disrupts an E2F-driven oncogenic transcriptional program and inhibits tumor growth. Our results establish LMS PDX as valuable preclinical models and identify strategies to discover novel vulnerabilities in this disease. These data support the clinical assessment of transcriptional CDK inhibitors as a therapeutic strategy for patients with LMS. ©2022 American Association for Cancer Research.

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