Consensus molecular subtype 4 (CMS4)-targeted therapy in primary colon cancer: A proof-of-concept study

Niek A Peters; Alexander Constantinides; Inge Ubink; Joyce van Kuik; Haiko J Bloemendal; Joyce M van Dodewaard; Menno A Brink; Thijs P Schwartz; Martijn P J K Lolkema; Miangela M Lacle; Leon M Moons; Joost Geesing; Wilhelmina M U van Grevenstein; Jeanine M L Roodhart; Miriam Koopman; Sjoerd G Elias; Inne H M Borel Rinkes; Onno Kranenburg

doi:10.3389/fonc.2022.969855

Consensus molecular subtype 4 (CMS4)-targeted therapy in primary colon cancer: A proof-of-concept study

Front Oncol. 2022 Sep 6:12:969855. doi: 10.3389/fonc.2022.969855. eCollection 2022.

Authors

Niek A Peters¹, Alexander Constantinides¹, Inge Ubink¹, Joyce van Kuik², Haiko J Bloemendal^{3

4}, Joyce M van Dodewaard³, Menno A Brink⁵, Thijs P Schwartz⁵, Martijn P J K Lolkema⁶, Miangela M Lacle², Leon M Moons⁷, Joost Geesing⁸, Wilhelmina M U van Grevenstein⁹, Jeanine M L Roodhart^{1

10}, Miriam Koopman¹⁰, Sjoerd G Elias¹¹, Inne H M Borel Rinkes^{1

9}, Onno Kranenburg¹

Affiliations

¹ Lab Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
² Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
³ Department of Internal Medicine, Meander Medical Center, Amersfoort, Netherlands.
⁴ Department of Internal Medicine/Oncology, Radboud University Medical Center Nijmegen, Nijmegen, Netherlands.
⁵ Department of Gastroenterology, Meander Medical Center, Amersfoort, Netherlands.
⁶ Department of Medical Oncology, Erasmus Medical Center, Rotterdam, Netherlands.
⁷ Department of Gastroenterology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
⁸ Department of Gastroenterology, Diakonessenhuis, Utrecht, Netherlands.
⁹ Department of Surgical Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
¹⁰ Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
¹¹ Julius Centre for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

Abstract

Background: Mesenchymal Consensus Molecular Subtype 4 (CMS4) colon cancer is associated with poor prognosis and therapy resistance. In this proof-of-concept study, we assessed whether a rationally chosen drug could mitigate the distinguishing molecular features of primary CMS4 colon cancer.

Methods: In the ImPACCT trial, informed consent was obtained for molecular subtyping at initial diagnosis of colon cancer using a validated RT-qPCR CMS4-test on three biopsies per tumor (Phase-1, n=69 patients), and for neoadjuvant CMS4-targeting therapy with imatinib (Phase-2, n=5). Pre- and post-treatment tumor biopsies were analyzed by RNA-sequencing and immunohistochemistry. Imatinib-induced gene expression changes were associated with molecular subtypes and survival in an independent cohort of 3232 primary colon cancer.

Results: The CMS4-test classified 52/172 biopsies as CMS4 (30%). Five patients consented to imatinib treatment prior to surgery, yielding 15 pre- and 15 post-treatment samples for molecular analysis. Imatinib treatment caused significant suppression of mesenchymal genes and upregulation of genes encoding epithelial junctions. The gene expression changes induced by imatinib were associated with improved survival and a shift from CMS4 to CMS2.

Conclusion: Imatinib may have value as a CMS-switching drug in primary colon cancer and induces a gene expression program that is associated with improved survival.

Keywords: ImPACCT; colorectal cancer; consensus molecular subtype 4; imatinib; platelet-derived growth factor receptor (PDGFR).

Copyright © 2022 Peters, Constantinides, Ubink, van Kuik, Bloemendal, van Dodewaard, Brink, Schwartz, Lolkema, Lacle, Moons, Geesing, van Grevenstein, Roodhart, Koopman, Elias, Borel Rinkes and Kranenburg.