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, 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
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).
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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.
Figures
References
- Guinney J, Dienstmann R, Wang X, de Reynies A, Schlicker A, Soneson C, et al. . The consensus molecular subtypes of colorectal cancer. Nat Med (2015) 21(11):1350–6. doi: 10.1038/nm.3967
- Trinh A, Trumpi K, De Sousa EMF, Wang X, de Jong JH, Fessler E, et al. . Practical and robust identification of molecular subtypes in colorectal cancer by immunohistochemistry. Clin Cancer Res an Off J Am Assoc Cancer Res (2017) 23(2):387–98. doi: 10.1158/1078-0432.CCR-16-0680
- Song N, Pogue-Geile KL, Gavin PG, Yothers G, Kim SR, Johnson NL, et al. . Clinical outcome from oxaliplatin treatment in stage Ii/Iii colon cancer according to intrinsic subtypes: Secondary analysis of nsabp c-07/Nrg oncology randomized clinical trial. JAMA Oncol (2016) 2(9):1162–9. doi: 10.1001/jamaoncol.2016.2314
- Ten Hoorn S, de Back TR, Sommeijer DW, Vermeulen L. Clinical value of consensus molecular subtypes in colorectal cancer: A systematic review and meta-analysis. J Natl Cancer Institute (2021) 114(4):503–16. doi: 10.1093/jnci/djab106
- Calon A, Lonardo E, Berenguer-Llergo A, Espinet E, Hernando-Momblona X, Iglesias M, et al. . Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat Genet (2015) 47(4):320–9. doi: 10.1038/ng.3225
- Isella C, Terrasi A, Bellomo SE, Petti C, Galatola G, Muratore A, et al. . Stromal contribution to the colorectal cancer transcriptome. Nat Genet (2015) 47(4):312–9. doi: 10.1038/ng.3224
- Steller EJ, Raats DA, Koster J, Rutten B, Govaert KM, Emmink BL, et al. . Pdgfrb promotes liver metastasis formation of mesenchymal-like colorectal tumor cells. Neoplasia (2013) 15(2):204–17. doi: 10.1593/neo.121726
- Fatrai S, van Schelven SJ, Ubink I, Govaert KM, Raats D, Koster J, et al. . Maintenance of clonogenic kit(+) human colon tumor cells requires secretion of stem cell factor by differentiated tumor cells. Gastroenterology (2015) 149(3):692–704. doi: 10.1053/j.gastro.2015.05.003
- Ubink I, Elias SG, Moelans CB, Lacle MM, van Grevenstein WMU, van Diest PJ, et al. . A novel diagnostic tool for selecting patients with mesenchymal-type colon cancer reveals intratumor subtype heterogeneity. J Natl Cancer Inst (2017) 109(8):1–8. doi: 10.1093/jnci/djw303
- Heldin CH. Targeting the pdgf signaling pathway in the treatment of non-malignant diseases. J Neuroimmune Pharmacol (2014) 9(2):69–79. doi: 10.1007/s11481-013-9484-2
- Kitadai Y, Sasaki T, Kuwai T, Nakamura T, Bucana CD, Fidler IJ. Targeting the expression of platelet-derived growth factor receptor by reactive stroma inhibits growth and metastasis of human colon carcinoma. AmJPathol (2006) 169(6):2054–65. doi: 10.2353/ajpath.2006.060653[doi
- Xing S, Wang C, Tang H, Guo J, Liu X, Yi F, et al. . Down-regulation of pdgfrbeta suppresses invasion and migration in osteosarcoma cells by influencing epithelial-mesenchymal transition. FEBS Open Bio (2020) 10(9):1748–57. doi: 10.1002/2211-5463.12915
- Hou H, Jia D, Yan W, Zhang X, Wang C, Li Y, et al. . Kit/Pdgfra/Kdr amplification defines a novel molecular subtype of adenoid cystic carcinoma patients who may benefit from treatment with tyrosine kinase inhibitors. Trans Cancer Res (2020) 9(8):4703–14. doi: 10.21037/tcr-20-637
- Nehoff H, Parayath NN, McConnell MJ, Taurin S, Greish K. A combination of tyrosine kinase inhibitors, crizotinib and dasatinib for the treatment of glioblastoma multiforme. Oncotarget (2015) 6(35):37948–64. doi: 10.18632/oncotarget.5698
- Dunne PD, McArt DG, Bradley CA, O'Reilly PG, Barrett HL, Cummins R, et al. . Challenging the cancer molecular stratification dogma: Intratumoral heterogeneity undermines consensus molecular subtypes and potential diagnostic value in colorectal cancer. Clin Cancer Res an Off J Am Assoc Cancer Res (2016) 22(16):4095–104. doi: 10.1158/1078-0432.CCR-16-0032
- Marisa L, Blum Y, Taieb J, Ayadi M, Pilati C, Le Malicot K, et al. . Intratumor cms heterogeneity impacts patient prognosis in localized colon cancer. Clin Cancer Res an Off J Am Assoc Cancer Res (2021) 27(17):4768–80. doi: 10.1158/1078-0432.CCR-21-0529
- Trumpi K, Ubink I, Trinh A, Djafarihamedani M, Jongen JM, Govaert KM, et al. . Neoadjuvant chemotherapy affects molecular classification of colorectal tumors. Oncogenesis (2017) 6(7):e357. doi: 10.1038/oncsis.2017.48
- Schlicker A, Ellappalayam A, Beumer IJ, Snel MHJ, Mittempergher L, Diosdado B, et al. . Investigating the concordance in molecular subtypes of primary colorectal tumors and their matched synchronous liver metastasis. Int J Cancer (2020) 147(8):2303–15. doi: 10.1002/ijc.33003
- Eide PW, Moosavi SH, Eilertsen IA, Brunsell TH, Langerud J, Berg KCG, et al. . Metastatic heterogeneity of the consensus molecular subtypes of colorectal cancer. NPJ Genom Med (2021) 6(1):59. doi: 10.1038/s41525-021-00223-7
- Ubink I, Bloemendal HJ, Elias SG, Brink MA, Schwartz MP, Holierhoek YCW, et al. . Imatinib treatment of poor prognosis mesenchymal-type primary colon cancer: A proof-of-Concept study in the preoperative window period (Impacct). BMC Cancer (2017) 17(1):282. doi: 10.1186/s12885-017-3264-y
- Chen EC, Karl TA, Kalisky T, Gupta SK, O'Brien CA, Longacre TA, et al. . Kit signaling promotes growth of colon xenograft tumors in mice and is up-regulated in a subset of human colon cancers. Gastroenterology (2015) 149(3):705–17 e2. doi: 10.1053/j.gastro.2015.05.042
- Hoehler T, von Wichert G, Schimanski C, Kanzler S, Moehler MH, Hinke A, et al. . Phase I/Ii trial of capecitabine and oxaliplatin in combination with bevacizumab and imatinib in patients with metastatic colorectal cancer: Aio krk 0205. Br J Cancer (2013) 109(6):1408–13. doi: 10.1038/bjc.2013.409
- Michael M, Zalcberg J, Gibbs P, Lipton L, Gouillou M, Jefford M, et al. . A phase I trial of imatinib in combination with Mfolfox6-bevacizumab in patients with advanced colorectal cancer. Cancer ChemotherPharmacol (2013) 71(2):321–30. doi: 10.1007/s00280-012-2009-5[doi
- Marisa L, de Reynies A, Duval A, Selves J, Gaub MP, Vescovo L, et al. . Gene expression classification of colon cancer into molecular subtypes: Characterization, validation, and prognostic value. PloS Med (2013) 10(5):e1001453. doi: 10.1371/journal.pmed.1001453
- Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature (2012) 487(7407):330–7. doi: 10.1038/nature11252
- Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, et al. . Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol (2011) 29(11):1046–51. doi: 10.1038/nbt.1990
- Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for rna-seq data with Deseq2. Genome Biol (2014) 15(12):550. doi: 10.1186/s13059-014-0550-8
- Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. . Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U.S.A. (2005) 102(43):15545–50. doi: 10.1073/pnas.0506580102
- Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, et al. . Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity (2013) 39(4):782–95. doi: 10.1016/j.immuni.2013.10.003
- Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, et al. . Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell (2014) 158(5):1110–22. doi: 10.1016/j.cell.2014.07.013
- Van der Flier LG, Sabates-Bellver J, Oving I, Haegebarth A, De Palo M, Anti M, et al. . The intestinal Wnt/Tcf signature. Gastroenterology (2007) 132(2):628–32. doi: 10.1053/j.gastro.2006.08.039
- Kanehisa M, Furumichi M, Sato Y, Ishiguro-Watanabe M, Tanabe M. Kegg: Integrating viruses and cellular organisms. Nucleic Acids Res (2021) 49(D1):D545–D51. doi: 10.1093/nar/gkaa970
- Fonseca BD, Smith EM, Yelle N, Alain T, Bushell M, Pause A. The ever-evolving role of mtor in translation. Semin Cell Dev Biol (2014) 36:102–12. doi: 10.1016/j.semcdb.2014.09.014
- Lorenz DJ, Datta S, Harkema SJ. Marginal association measures for clustered data. Stat Med (2011) 30(27):3181–91. doi: 10.1002/sim.4368
- Dienstmann R, Vermeulen L, Guinney J, Kopetz S, Tejpar S, Tabernero J. Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat Rev Cancer (2017) 17(2):79–92. doi: 10.1038/nrc.2016.126
- Anjomshoaa A, Nasri S, Humar B, McCall JL, Chatterjee A, Yoon HS, et al. . Slow proliferation as a biological feature of colorectal cancer metastasis. Br J Cancer (2009) 101(5):822–8. doi: 10.1038/sj.bjc.6605229
- Melo DSE, Colak S, Buikhuisen J, Koster J, Cameron K, de Jong JH, et al. . Methylation of cancer-Stem-Cell-Associated wnt target genes predicts poor prognosis in colorectal cancer patients. Cell Stem Cell (2011) 9(5):476–85. doi: 10.1016/j.stem.2011.10.008
- Emmink BL, van Houdt WJ, Vries RG, Hoogwater FJ, Govaert KM, Verheem A, et al. . Differentiated human colorectal cancer cells protect tumor-initiating cells from irinotecan. Gastroenterology (2011) 141(1):269–78. doi: 10.1053/j.gastro.2011.03.052
- Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P. The molecular signatures database (Msigdb) hallmark gene set collection. Cell Syst (2015) 1(6):417–25. doi: 10.1016/j.cels.2015.12.004
- Thomas LW, Esposito C, Stephen JM, Costa ASH, Frezza C, Blacker TS, et al. . Chchd4 regulates tumour proliferation and emt-related phenotypes, through respiratory chain-mediated metabolism. Cancer Metab (2019) 7:7. doi: 10.1186/s40170-019-0200-4
- Bankhead P, Loughrey MB, Fernandez JA, Dombrowski Y, McArt DG, Dunne PD, et al. . Qupath: Open source software for digital pathology image analysis. Sci Rep (2017) 7(1):16878. doi: 10.1038/s41598-017-17204-5
- Magnuson B, Ekim B, Fingar DC. Regulation and function of ribosomal protein S6 kinase (S6k) within mtor signalling networks. Biochem J (2012) 441(1):1–21. doi: 10.1042/BJ20110892
- Faller WJ, Jackson TJ, Knight JR, Ridgway RA, Jamieson T, Karim SA, et al. . Mtorc1-mediated translational elongation limits intestinal tumour initiation and growth. Nature (2015) 517(7535):497–500. doi: 10.1038/nature13896
- Evdokimova V, Tognon C, Ng T, Sorensen PH. Reduced proliferation and enhanced migration: Two sides of the same coin? molecular mechanisms of metastatic progression by yb-1. Cell Cycle (2009) 8(18):2901–6. doi: 10.4161/cc.8.18.9537
- Shiwarski DJ, Shao C, Bill A, Kim J, Xiao D, Bertrand CA, et al. . To "Grow" or "Go": Tmem16a expression as a switch between tumor growth and metastasis in scchn. Clin Cancer Res an Off J Am Assoc Cancer Res (2014) 20(17):4673–88. doi: 10.1158/1078-0432.CCR-14-0363
- Cargnello M, Tcherkezian J, Roux PP. The expanding role of mtor in cancer cell growth and proliferation. Mutagenesis (2015) 30(2):169–76. doi: 10.1093/mutage/geu045
- Li J, Dang Y, Gao J, Li Y, Zou J, Shen L. Pi3k/Akt/Mtor pathway is activated after imatinib secondary resistance in gastrointestinal stromal tumors (Gists). Med Oncol (2015) 32(4):111. doi: 10.1007/s12032-015-0554-6
- Burchert A, Wang Y, Cai D, von Bubnoff N, Paschka P, Muller-Brusselbach S, et al. . Compensatory Pi3-Kinase/Akt/Mtor activation regulates imatinib resistance development. Leukemia (2005) 19(10):1774–82. doi: 10.1038/sj.leu.2403898
- Singh P, Kumar V, Gupta SK, Kumari G, Verma M. Combating tki resistance in cml by inhibiting the Pi3k/Akt/Mtor pathway in combination with tkis: A review. Med Oncol (2021) 38(1):10. doi: 10.1007/s12032-021-01462-5
- Schoffski P, Reichardt P, Blay JY, Dumez H, Morgan JA, Ray-Coquard I, et al. . A phase I-ii study of everolimus (Rad001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors. Ann Oncol Off J Eur Soc Med Oncol / ESMO (2010) 21(10):1990–8. doi: 10.1093/annonc/mdq076
- Piskol R, Huw L, Sergin I, Kljin C, Modrusan Z, Kim D, et al. . A clinically applicable gene-expression classifier reveals intrinsic and extrinsic contributions to consensus molecular subtypes in primary and metastatic colon cancer. Clin Cancer Res an Off J Am Assoc Cancer Res (2019) 25(14):4431–42. doi: 10.1158/1078-0432.CCR-18-3032
- Sirinukunwattana K, Domingo E, Richman SD, Redmond KL, Blake A, Verrill C, et al. . Image-based consensus molecular subtype (Imcms) classification of colorectal cancer using deep learning. Gut (2021) 70(3):544–54. doi: 10.1136/gutjnl-2019-319866
- Strating E, Wassenaar E, Verhagen M, Rauwerdink P, van Schelven S, de Hingh I. Strating eea. fibroblast activation protein identifies consensus molecular subtype 4 in colorectal cancer and allows its detection by 68ga-fapi pet imaging. Br J Cancer (2022) 127(1):145–55. doi: 10.1038/s41416-022-01748-z
Source: PubMed