2. Academic Validation
  3. Concurrent inhibition of CDK2 adds to the anti-tumour activity of CDK4/6 inhibition in GIST

Concurrent inhibition of CDK2 adds to the anti-tumour activity of CDK4/6 inhibition in GIST

  • Br J Cancer. 2022 Sep 29. doi: 10.1038/s41416-022-01990-5.
Inga-Marie Schaefer 1,  Matthew L Hemming 2 3,  Meijun Z Lundberg 4,  Matthew P Serrata 5,  Isabel Goldaracena 5,  Ninning Liu 5,  Peng Yin 5,  Joao A Paulo 6,  Steven P Gygi 6,  Suzanne George 2 3,  Jeffrey A Morgan 2 3,  Monica M Bertagnolli 7,  Ewa T Sicinska 8,  Chen Chu 9 10,  Shanshan Zheng 9 10,  Adrian Mariño-Enríquez 4,  Jason L Hornick 4 3,  Chandrajit P Raut 3 7,  Wen-Bin Ou 4 11,  George D Demetri 2 3 12,  Sinem K Saka 5 13,  Jonathan A Fletcher 4 3
Affiliations

Affiliations

  • 1 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. ischaefer@bwh.harvard.edu.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • 3 Sarcoma Center, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA.
  • 4 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 5 Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
  • 6 Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
  • 7 Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 8 Department of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 9 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 10 Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • 11 Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China.
  • 12 Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.
  • 13 European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
PMID: 36175617 DOI: 10.1038/s41416-022-01990-5
Abstract

Background: Advanced gastrointestinal stromal tumour (GIST) is characterised by genomic perturbations of key cell cycle regulators. Oncogenic activation of CDK4/6 results in RB1 inactivation and cell cycle progression. Given that single-agent CDK4/6 inhibitor therapy failed to show clinical activity in advanced GIST, we evaluated strategies for maximising response to therapeutic CDK4/6 inhibition.

Methods: Targeted next-generation Sequencing and multiplexed protein imaging were used to detect cell cycle regulator aberrations in GIST clinical samples. The impact of inhibitors of CDK2, CDK4 and CDK2/4/6 was determined through cell proliferation and protein detection assays. CDK-inhibitor resistance mechanisms were characterised in GIST cell lines after long-term exposure.

Results: We identify recurrent genomic aberrations in cell cycle regulators causing co-activation of the CDK2 and CDK4/6 pathways in clinical GIST samples. Therapeutic co-targeting of CDK2 and CDK4/6 is synergistic in GIST cell lines with intact RB1, through inhibition of RB1 hyperphosphorylation and cell proliferation. Moreover, RB1 inactivation and a novel oncogenic cyclin D1 resulting from an intragenic rearrangement (CCND1::chr11.g:70025223) are mechanisms of acquired CDK-inhibitor resistance in GIST.

Conclusions: These studies establish the biological rationale for CDK2 and CDK4/6 co-inhibition as a therapeutic strategy in patients with advanced GIST, including metastatic GIST progressing on tyrosine kinase inhibitors.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-114177
    99.98%, CDK2/4/6 Inhibitor
    CDK