Kolorektal Kanserin Proteomik Profili: Kişiselleştirilmiş Tedavi için İlaçlanabilir Biyobelirteçlerin Keşfi

Yıl 2025, Cilt: 15 Sayı: 1, 519 - 535, 15.03.2025

Abdulkadir Elmas

https://doi.org/10.31466/kfbd.1608816

Öz

Kolorektal kanser (CRC), ileri evre hastalar için sınırlı tedavi seçenekleri nedeniyle küresel ölçekte önemli bir sağlık sorunu olmaya devam etmektedir. Genomik ve transkriptomik analizler hedef belirlemede değerli bir rol oynasa da, proteomik düzeydeki değişimler tümör biyolojisini daha doğrudan yansıtmakta ve terapötik açıdan daha uygulanabilir fırsatlar sunmaktadır. Bu çalışmada, 102 birincil CRC hastasına ait, tümör ve eşlenmiş normal dokuları içeren kütle spektrometresi proteomik verilerini analiz ederek, hasta kinomu üzerine odaklanarak sistematik bir şekilde aşırı ifade (eksprese) edilen, ilaçlanabilir terapötik hedefleri tanımladık. OPPTI metodunu kullanarak, mevcut ilaçlarla hedeflenebilir olan FGR, EPHA2 ve PBK gibi 16 kinazı içeren, toplamda 31 kinazın belirgin şekilde aşırı ifade edildiğini tespit ettik. Ayrıca, ERAP2, FLG ve MT1H gibi 253’ü ilaçlanabilir olan 884 kinaz dışı proteinin aşırı ifade edildiğini ortaya koyduk. Diferansiyel ifade analizi, 165 düzensiz kinaz ve 3,903 kinaz dışı proteini belirlerken, MET ve STK3, önemli derecede artış gösteren potansiyel adaylar olarak öne çıktı. Diferansiyel ifade ve aşırı ifade analizlerini birleştirerek, EPHA2 ve MET gibi ilaçlanabilir hedeflerden oluşan bir grup belirledik; bu hedeflerin inhibisyonu, umut verici preklinik etkinlik göstermiştir. Bu kapsamlı proteomik çalışma, CRC’de yeni terapötik hedeflerin keşfi için bir kaynak sunmakta ve klinik olarak uygulanabilir protein düzeyindeki değişikliklerin tanımlanması yoluyla daha kişiselleştirilmiş müdahalelere yönelik bir çerçeve sağlamaktadır.

Anahtar Kelimeler

Kolorektal kanser (CRC), Proteomik analiz, Kişiselleştirilmiş tedavi, İlaç hedefleri, Tümör biyobelirteçleri

Proteomic Profiling in Colorectal Cancer: Identifying Druggable Biomarkers for Personalized Therapy

Öz

Colorectal cancer (CRC) remains a major global health challenge, with limited treatment options for advanced-stage patients. While genomic and transcriptomic analyses aid in target identification, proteomic alterations offer a more direct link to tumor biology and therapeutic opportunities. In this study, we analyzed mass spectrometry-based proteomics data from 102 primary CRC patients, including tumor and matched normal tissues, to systematically identify overexpressed, druggable therapeutic targets, with a particular focus on the patient kinome. Using the OPPTI approach, we discovered 31 kinases with notable overexpression, including 16 currently targetable by existing drugs, such as FGR, EPHA2, and PBK. Furthermore, we revealed 884 overexpressed non-kinase proteins, 253 of which are druggable, including ERAP2, FLG, and MT1H. Differential expression analysis identified 165 dysregulated kinases and 3,903 non-kinase proteins, with MET and STK3 emerging as potential candidates due to their substantial upregulation. Integrating differential expression and overexpression analyses, we highlighted a cohort of druggable targets, including EPHA2 and MET, whose inhibition has shown promising preclinical efficacy. This comprehensive proteomic study provides a resource for novel therapeutic target discovery in CRC, offering a framework for more personalized interventions through the identification of clinically actionable protein-level alterations.

Anahtar Kelimeler

Colorectal cancer (CRC), Proteomics, Personalized therapy, Drug targets, Tumor biomarkers

Kaynakça

• Benjamini, Y., & Hochberg, Y. (1995). Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society Series B: Statistical Methodology, 57(1), 289–300. https://doi.org/10.1111/j.2517-6161.1995.tb02031.x
• Bhullar, K. S., Lagarón, N. O., McGowan, E. M., Parmar, I., Jha, A., Hubbard, B. P., & Rupasinghe, H. P. V. (2018). Kinase-targeted cancer therapies: Progress, challenges and future directions. In Molecular Cancer (Vol. 17, Issue 1). BioMed Central Ltd. https://doi.org/10.1186/s12943-018-0804-2
• Cotto, K. C., Wagner, A. H., Feng, Y.-Y., Kiwala, S., Coffman, A. C., Spies, G., Wollam, A., Spies, N. C., Griffith, O. L., & Griffith, M. (2018). DGIdb 3.0: a redesign and expansion of the drug-gene interaction database. Nucleic Acids Research, 46(D1), D1068–D1073. https://doi.org/10.1093/nar/gkx1143
• De Roock, W., Claes, B., Bernasconi, D., De Schutter, J., Biesmans, B., Fountzilas, G., Kalogeras, K. T., Kotoula, V., Papamichael, D., Laurent-Puig, P., Penault-Llorca, F., Rougier, P., Vincenzi, B., Santini, D., Tonini, G., Cappuzzo, F., Frattini, M., Molinari, F., Saletti, P., … Tejpar, S. (2010). Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. The Lancet Oncology, 11(8), 753–762. https://doi.org/10.1016/S1470-2045(10)70130-3
• Delord, J.-P., Argilés, G., Fayette, J., Wirth, L., Kasper, S., Siena, S., Mesia, R., Berardi, R., Cervantes, A., Dekervel, J., Zhao, S., Sun, Y., Hao, H.-X., Tiedt, R., Vicente, S., Myers, A., & Siu, L. L. (2020). A phase 1b study of the MET inhibitor capmatinib combined with cetuximab in patients with MET-positive colorectal cancer who had progressed following anti-EGFR monoclonal antibody treatment. Investigational New Drugs, 38(6), 1774–1783. https://doi.org/10.1007/s10637-020-00928-z
• Elmas, A., Tharakan, S., Jaladanki, S., Galsky, M. D., Liu, T., & Huang, K.-L. (2021). Pan-cancer proteogenomic investigations identify post-transcriptional kinase targets. Communications Biology, 4(1), 1112. https://doi.org/10.1038/s42003-021-02636-7
• Fruci, D., Giacomini, P., Nicotra, M. R., Forloni, M., Fraioli, R., Saveanu, L., van Endert, P., & Natali, P. G. (2008). Altered expression of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 in transformed non-lymphoid human tissues. Journal of Cellular Physiology, 216(3), 742–749. https://doi.org/10.1002/jcp.21454
• Gallo, S., Folco, C. B., & Crepaldi, T. (2024). The MET Oncogene: An Update on Targeting Strategies. Pharmaceuticals, 17(11), 1473. https://doi.org/10.3390/ph17111473
• Guo, X., Yang, Y., Tang, J., & Xiang, J. (2024). Ephs in cancer progression: complexity and context-dependent nature in signaling, angiogenesis and immunity. In Cell Communication and Signaling (Vol. 22, Issue 1). BioMed Central Ltd. https://doi.org/10.1186/s12964-024-01580-3
• Huang, K.-L., Li, S., Mertins, P., Cao, S., Gunawardena, H. P., Ruggles, K. V, Mani, D. R., Clauser, K. R., Tanioka, M., Usary, J., Kavuri, S. M., Xie, L., Yoon, C., Qiao, J. W., Wrobel, J., Wyczalkowski, M. A., Erdmann-Gilmore, P., Snider, J. E., Hoog, J., … Ding, L. (2017). Proteogenomic integration reveals therapeutic targets in breast cancer xenografts. Nature Communications, 8, 14864. https://doi.org/10.1038/ncomms14864
• Koshino, A., Nagano, A., Ota, A., Hyodo, T., Ueki, A., Komura, M., Sugimura-Nagata, A., Ebi, M., Ogasawara, N., Kasai, K., Hosokawa, Y., Kasugai, K., Takahashi, S., & Inaguma, S. (2022). PBK Enhances Cellular Proliferation With Histone H3 Phosphorylation and Suppresses Migration and Invasion With CDH1 Stabilization in Colorectal Cancer. Frontiers in Pharmacology, 12. https://doi.org/10.3389/fphar.2021.772926
• Lee, E. D. (2017). Endoplasmic Reticulum Aminopeptidase 2, a common immunological link to adverse pregnancy outcomes and cancer clearance? Placenta, 56, 40–43. https://doi.org/10.1016/j.placenta.2017.03.012
• Liu, Y., Li, J., & Qi, J. (2019). The role of the class I Wnt pathway antagonist sFRP4 in colorectal cancer. Digestive Medicine Research, 2, 18–18. https://doi.org/10.21037/dmr.2019.08.01
• Liu, Y., Lv, H., Liu, X., Xu, L., Li, T., Zhou, H., Zhu, H., Hao, C., Lin, C., & Zhang, Y. (2024). The RP11-417E7.1/THBS2 signaling pathway promotes colorectal cancer metastasis by activating the Wnt/β-catenin pathway and facilitating exosome-mediated M2 macrophage polarization. Journal of Experimental and Clinical Cancer Research, 43(1). https://doi.org/10.1186/s13046-024-03107-7
• Manning, G., Whyte, D. B., Martinez, R., Hunter, T., & Sudarsanam, S. (2002). The protein kinase complement of the human genome. Science (New York, N.Y.), 298(5600), 1912–1934. https://doi.org/10.1126/science.1075762
• Mertins, P., Yang, F., Liu, T., Mani, D. R., Petyuk, V. A., Gillette, M. A., Clauser, K. R., Qiao, J. W., Gritsenko, M. A., Moore, R. J., Levine, D. A., Townsend, R., Erdmann-Gilmore, P., Snider, J. E., Davies, S. R., Ruggles, K. V, Fenyo, D., Kitchens, R. T., Li, S., … Carr, S. A. (2014). Ischemia in tumors induces early and sustained phosphorylation changes in stress kinase pathways but does not affect global protein levels. Molecular & Cellular Proteomics : MCP, 13(7), 1690–1704. https://doi.org/10.1074/mcp.M113.036392
• Morgan, E., Arnold, M., Gini, A., Lorenzoni, V., Cabasag, C. J., Laversanne, M., Vignat, J., Ferlay, J., Murphy, N., & Bray, F. (2023). Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. Gut, 72(2), 338–344. https://doi.org/10.1136/gutjnl-2022-327736
• Muzny, D. M., Bainbridge, M. N., Chang, K., Dinh, H. H., Drummond, J. A., Fowler, G., Kovar, C. L., Lewis, L. R., Morgan, M. B., Newsham, I. F., Reid, J. G., Santibanez, J., Shinbrot, E., Trevino, L. R., Wu, Y. Q., Wang, M., Gunaratne, P., Donehower, L. A., Creighton, C. J., … Thomson., E. (2012). Comprehensive molecular characterization of human colon and rectal cancer. Nature, 487(7407), 330–337. https://doi.org/10.1038/nature11252
• Nunes, L., Li, F., Wu, M., Luo, T., Hammarström, K., Torell, E., Ljuslinder, I., Mezheyeuski, A., Edqvist, P.-H., Löfgren-Burström, A., Zingmark, C., Edin, S., Larsson, C., Mathot, L., Osterman, E., Osterlund, E., Ljungström, V., Neves, I., Yacoub, N., … Sjöblom, T. (2024). Prognostic genome and transcriptome signatures in colorectal cancers. Nature, 633(8028), 137–146. https://doi.org/10.1038/s41586-024-07769-3
• Qu, H. L., Hasen, G. W., Hou, Y. Y., & Zhang, C. X. (2022). THBS2 promotes cell migration and invasion in colorectal cancer via modulating Wnt/β-catenin signaling pathway. Kaohsiung Journal of Medical Sciences, 38(5), 469–478. https://doi.org/10.1002/kjm2.12528
• Ritchie, M. E., Phipson, B., Wu, D., Hu, Y., Law, C. W., Shi, W., & Smyth, G. K. (2015). limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Research, 43(7), e47. https://doi.org/10.1093/nar/gkv007
• Roseweir, A. K., Powell, A. G. M. T., Horstman, S. L., Inthagard, J., Park, J. H., McMillan, D. C., Horgan, P. G., & Edwards, J. (2019). Src family kinases, HCK and FGR, associate with local inflammation and tumour progression in colorectal cancer. Cellular Signalling, 56, 15–22. https://doi.org/10.1016/j.cellsig.2019.01.007
• Ruggles, K. V., Krug, K., Wang, X., Clauser, K. R., Wang, J., Payne, S. H., Fenyö, D., Zhang, B., & Mani, D. R. (2017). Methods, Tools and Current Perspectives in Proteogenomics. Molecular & Cellular Proteomics, 16(6), 959–981. https://doi.org/10.1074/mcp.MR117.000024
• Rustgi, A. K. (2007). The genetics of hereditary colon cancer. In Genes and Development (Vol. 21, Issue 20, pp. 2525–2538). https://doi.org/10.1101/gad.1593107
• Sanchez-Vega, F., Mina, M., Armenia, J., Chatila, W. K., Luna, A., La, K. C., Dimitriadoy, S., Liu, D. L., Kantheti, H. S., Saghafinia, S., Chakravarty, D., Daian, F., Gao, Q., Bailey, M. H., Liang, W.-W., Foltz, S. M., Shmulevich, I., Ding, L., Heins, Z., … Schultz, N. (2018). Oncogenic Signaling Pathways in The Cancer Genome Atlas. Cell, 173(2), 321-337.e10. https://doi.org/10.1016/j.cell.2018.03.035
• Siegel, R. L., Wagle, N. S., Cercek, A., Smith, R. A., & Jemal, A. (2023). Colorectal cancer statistics, 2023. CA: A Cancer Journal for Clinicians, 73(3), 233–254. https://doi.org/10.3322/caac.21772
• Tröster, A., Jores, N., Mineev, K. S., Sreeramulu, S., DiPrima, M., Tosato, G., & Schwalbe, H. (2023). Targeting EPHA2 with Kinase Inhibitors in Colorectal Cancer. ChemMedChem, 18(23). https://doi.org/10.1002/cmdc.202300420
• Van Cutsem, E., Cervantes, A., Adam, R., Sobrero, A., Van Krieken, J. H., Aderka, D., Aranda Aguilar, E., Bardelli, A., Benson, A., Bodoky, G., Ciardiello, F., D’Hoore, A., Diaz-Rubio, E., Douillard, J.-Y., Ducreux, M., Falcone, A., Grothey, A., Gruenberger, T., Haustermans, K., … Arnold, D. (2016). ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Annals of Oncology, 27(8), 1386–1422. https://doi.org/10.1093/annonc/mdw235
• Vasaikar, S., Huang, C., Wang, X., Petyuk, V. A., Savage, S. R., Wen, B., Dou, Y., Zhang, Y., Shi, Z., Arshad, O. A., Gritsenko, M. A., Zimmerman, L. J., McDermott, J. E., Clauss, T. R., Moore, R. J., Zhao, R., Monroe, M. E., Wang, Y.-T., Chambers, M. C., … Clinical Proteomic Tumor Analysis Consortium. (2019). Proteogenomic Analysis of Human Colon Cancer Reveals New Therapeutic Opportunities. Cell, 177(4), 1035-1049.e19. https://doi.org/10.1016/j.cell.2019.03.030
• Wang, K., Zheng, J., Yu, J., Wu, Y., Guo, J., Xu, Z., & Sun, X. (2020). Knockdown of MMP 1 inhibits the progression of colorectal cancer by suppressing the PI3K/Akt/c myc signaling pathway and EMT. Oncology Reports, 43(4), 1103–1112. https://doi.org/10.3892/or.2020.7490
• Weinstein, J. N., Collisson, E. A., Mills, G. B., Shaw, K. R. M., Ozenberger, B. A., Ellrott, K., Shmulevich, I., Sander, C., & Stuart, J. M. (2013). The Cancer Genome Atlas Pan-Cancer analysis project. Nature Genetics, 45(10), 1113–1120. https://doi.org/10.1038/ng.2764
• Xiao, T., Xiao, Y., Wang, W., Tang, Y. Y., Xiao, Z., & Su, M. (2020). Targeting EphA2 in cancer. In Journal of Hematology and Oncology (Vol. 13, Issue 1). BioMed Central. https://doi.org/10.1186/s13045-020-00944-9
• Yuan, Z., Hu, H., Zhu, Y., Zhang, W., Fang, Q., Qiao, T., Ma, T., Wang, M., Huang, R., Tang, Q., Gao, F., Zou, C., Gao, X., Wang, G., & Wang, X. (2021). Colorectal cancer cell intrinsic fibroblast activation protein alpha binds to Enolase1 and activates NF-κB pathway to promote metastasis. Cell Death and Disease, 12(6). https://doi.org/10.1038/s41419-021-03823-4
• Zhang, J., Yang, P. L., & Gray, N. S. (2009). Targeting cancer with small molecule kinase inhibitors. Nature Reviews Cancer, 9(1), 28–39. https://doi.org/10.1038/nrc2559
• Zhao, Z., Chu, Y., Feng, A., Zhang, S., Wu, H., Li, Z., Sun, M., Zhang, L., Chen, T., & Xu, M. (2024). STK3 kinase activation inhibits tumor proliferation through FOXO1-TP53INP1/P21 pathway in esophageal squamous cell carcinoma. Cellular Oncology, 47(4), 1295–1314. https://doi.org/10.1007/s13402-024-00928-8