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
  • 1. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
  • 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.

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