Chemotherapeutic Agents Targeting Intracellular Signaling Pathways

Yıl 2021, Cilt: 4 Sayı: 2, 175 - 184, 01.05.2021

Sevgi Uğur Mutluay , Leyla Didem Kozacı

https://doi.org/10.19127/bshealthscience.825971

Öz

In cancer treatment, conventional chemotherapeutics have been in clinical use since 1940s. Even though their efficacy has been established for many years, selectivity problem and serious side effects limit their use. Disadvantages of available therapies and need for novel anti-cancer drugs induced a shift in research towards that direction. Over the past 20 years, by shedding light on
molecular mechanisms of cancer, intracellular proteins, that might be targets for new drugs, have been defined. Of these targets, primary ones are; PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, Ubiquitin-Proteasom and Hedgehog pathways. These pathways and their downstream effectors shown to play a role in many cancer types. Protein kinases, which are involved in intracellular signaling pathways and found to be related to those pathways, are the molecules that are most studied. Many inhibitor molecules and/or monoclonal antibodies spesific to tyrosine and serine/theronine kinases have been developed and brought into use. Several members of tyrosine kinase family, which consists of around 20 subclasses, have been shown to be related to cancer. In this regard, prominent receptor tyrosine kinases can be sorted as EGFR, PDGFR, VEGFR, FLT3 and ALK. Other protein kinases; Src, BTK, CDK and AMPK have been reported to mediate critical processes in cancer development. Beside those targets, potential molecular targets and chemotherapeutic agents to these targets have been defined. Many molecules, that were developed to inhibit NOTCH, JAK-STAT, Nuclear Factor Kappa B, Wnt/ ß-Catenin pathways, Insulin, FGF, HGF, GSK-3 receptors, Protein Kinase C, Aurora Kinase and Hsp90 activity, are in stage of clinical study.

Anahtar Kelimeler

Cancer, Chemotherapy, Signaling pathways, Targeted therapy, Protein kinase inhibitors

Hücre İçi Sinyal Yolaklarını Hedefleyen Kemoterapötik Ajanlar

Öz

Kanser tedavisinde, konvansiyonel kemoterapötikler 1940’lı yıllardan beri klinikte kullanılmaktadırlar. Etkililikleri uzun yıllardır kanıtlanmış olsa da seçicilik sorunu ve ciddi yan etkilere yol açmaları bu ajanların kullanımını kısıtlar. Mevcut tedavilerin dezavantajları ve yeni anti-kanser ilaçlarına olan ihtiyaç araştırmaların bu yöne kaymasına neden olmuştur. Son 20 yılda kanserin
moleküler mekanizmalarının da aydınlatılması ile yeni ilaçlar için hedef olabilecek proteinler tanımlanmıştır. Bu hedeflerden başlıcaları PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, Ubikitin-Proteazom ve Hedgehog yolaklarıdır. Bu yolakların ve efektörlerinin birçok kanser tipinde rolü olduğu gösterilmiştir. Hücre içi sinyal mekanizmalarında görev alan ve bu yolaklarla ilişkili bulunan protein
kinazlar üzerlerinde en çok çalışma yapılan moleküllerdir. Tirozin ve serin/treonin kinazlara özgü birçok inhibitör molekül ve/veya monoklonal antikor geliştirilmiş ve kullanıma sunulmuştur. Yaklaşık 20 alt sınıftan oluşan reseptör tirozin kinazların (RTK) birçok üyesinin kanserle ilişkili olduğu gösterilmiştir. Bu bağlamda öne çıkan RTK’lar; EGFR, PDGFR, VEGFR, FLT3 ve ALK olarak sıralanabilir. Diğer protein kinazlardan Src, BTK, CDK ve AMPK’nın kanser gelişimi ile ilgili kritik süreçlere aracılık ettiği bildirilmiştir. Bu hedeflerin yanısıra potansiyel moleküler hedefler ve bu hedeflere yönelik kemoterapötik ajanlar da belirlenmiştir. NOTCH, JAK-STAT, Nükleer Faktör Kappa B, Wnt/ ß-Catenin yolaklarını, İnsülin, FGF, HGF, GSK-3 reseptörlerini, Protein Kinaz C, Aurora Kinaz ve Hsp90 aktivitesini inhibe etmeye yönelik geliştirilen birçok molekül klinik çalışma aşamasındadır.

Anahtar Kelimeler

Kanser, Kemoterapi, Sinyal yolakları, Hedefe yönelik tedavi, Protein kinaz inhibitörleri

Kaynakça

• Antar AI, Otrock ZK, Jabbour E, Mohty M, Bazarbachi B. 2020. FLT3 inhibitors in acute myeloid leukemia: ten frequently asked questions. Leukemia, 34: 682-696. DOI: 10.1038/s41375-019-0694-3.
• Arora A, Scholar EM. 2005. Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther, 315(3): 971‐979. DOI: 10.1124/jpet.105.084145.
• Asati V, Mahapatra DK, Bharti SK. 2016. PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives. Eur J Med Chem, 109: 314‐341. DOI: 10.1016/j.ejmech.2016.01.012.
• Ashkenazi A, Fairbrother WJ, Leverson JD, Souers AJ. 2017. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov, 16(4): 273‐284. DOI: 10.1038/nrd.2016.253.
• Bagnyukova TV, Serebriiskii IG, Zhou Y, Hopper-Borge EA, Golemis EA et al. 2010. Chemotherapy and signaling. How can targeted therapies supercharge cytotoxic agents? Cancer Biol Ther, 10(9): 839-853. DOI: 10.4161/cbt.10.9.13738.
• Baudino AT. 2015. Targeted cancer therapy: The next generation of cancer treatment. Curr Drug Discov Technol, 12(1) : 3-20.
• Burger JA, Wiestner A. 2018. Targeting B cell receptor signalling in cancer: preclinical and clinical advances. Nat Rev Cancer, 18(3): 148‐167. DOI: 10.1038/nrc.2017.121.
• Canavese M, Santo L, Raje N. 2012. Cyclin dependent kinases in cancer: potential for therapeutic intervention. Cancer Biol Ther, (7): 451‐457. DOI: 10.4161/cbt.19589.
• D’Assoro AB, Haddad T, Galanis E. 2016. Aurora-A Kinase as a Promising Therapeutic Target in Cancer. Front Oncol, 5(295): DOI: 10.3389/fonc.2015.00295.
• Du B, Jiang QL, Cleveland J, Liu BR, Zhang D. 2016. Targeting Toll-like receptors against cancer. J Cancer Metastasis, 2: 463-470. DOI: 10.20517/2394-4722.2016.62.
• Fox EM, Andrade J, Shupnik MA. 2009. Novel actions of estrogen to promote proliferation: integration of cytoplasmic and nuclear pathways. Steroids, 74(7): 622‐627. DOI: 10.1016/j.steroids.2008.10.014.
• Gocek E, Moulas AN, Studzinski GP. 2014. Non-receptor protein tyrosine kinases signaling pathways in normal and cancer cells. Crit Rev Clin Lab Sci, 51(3): 125‐137. DOI: 10.3109/10408363.2013.874403.
• Groner B, von Manstein V. 2017. Jak Stat signaling and cancer: Opportunities, benefits and side effects of targeted inhibition. Mol Cell Endocrinol, 451: 1‐14. DOI: 10.1016/j.mce.2017.05.033.
• Gupta S, Takebe N, Lorusso P. 2010. Targeting the hedgehog pathway in cancer. Ther Adv Med Oncol, 2(4): 237‐250. DOI: 10.1177/1758834010366430.
• Harvey AJ. 2019. Predictive biomarkers in oncology applications in precision medicine (ebook). Springer Nature Switzerland AG, 2019: 167-182. DOI: 10.1007/978-3-319-95228-4.
• Heldin CH. 2013. Targeting the PDGF signaling pathway in tumor treatment. Cell Commun Signal, 11: 97. DOI: 10.1186/1478-811X-11-97.
• Kang JH. 2014. Protein kinase C (PKC) isozymes and cancer. New J Sci, 2014: 231418. DOI: 10.1155/2014/231418.
• Keeton AB, Salter EA, Piazza GA. 2017. The RAS-effector interaction as a drug target. Cancer Res, 77(2): 221‐226. DOI: 10.1158/0008-5472.CAN-16-0938.
• Krishnamurthy N, Kurzrock R. 2018. Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors. Cancer Treat Rev, 62: 50‐60. DOI: 10.1016/j.ctrv.2017.11.002.
• Lanman BA, Allen JR, Allen JG, Amegadzie AK, Ashton KS, Booker SK. 2020. Discovery of a covalent inhibitor of KRASG12C (AMG 510) for the treatment of solid tumors. J Med Chem, 63(1): 52–65. DOI: 10.1021/acs.jmedchem.9b01180.
• Levitzki A, Klein S. 2010. Signal transduction therapy of cancer. Mol Aspects Med, 31(4): 287-329. DOI: 10.1016/j.mam.2010.04.001.
• Li F, Zhang J, Arfuso F, Chinnathambi A, Zayed ME. 2015. NF-κB in cancer therapy. Arch Toxicol, 89: 711-731. DOI: 10.1007/s00204-015-1470-4.
• Li W, Saud SM, Young MR, Chen G, Hua B. 2015. Targeting AMPK for cancer prevention and treatment. Oncotarget, 6(10): 7365‐7378. DOI: 10.18632/oncotarget.3629.
• Lu H. 2014. TLR Agonists for cancer immunotherapy: Tipping the balance between the immune stimulatory and inhibitory effects. Front Immunol, 5: 83. DOI: 10.3389/fimmu.2014.00083.
• Mahalingam D, Swords R, Carew JS, Nawrocki ST, Bhalla K, Giles FJ. 2009. Targeting HSP90 for cancer therapy. Br J Cancer, 100(10): 1523‐1529. DOI: 10.1038/sj.bjc.6605066.
• Manasanch EE, Orlowski RZ. 2017. Proteasome inhibitors in cancer therapy. Nat Rev Clin Oncol, 14(7): 417‐433. DOI: 10.1038/nrclinonc.2016.206.
• McCubrey JA, Steelman LS, Bertrand FE, Davis NM, Sokolosky M. 2014. GSK-3 as potential target for therapeutic intervention in cancer. Oncotarget, 5(10): 2881‐2911. DOI: 10.18632/oncotarget.2037.
• Montero JC, Seoane S, Ocaña A, Pandiella A. 2011. Inhibition of Src family kinases and receptor tyrosine kinases by dasatinib: possible combinations in solid tumors. Clin Cancer Res, 17 (17): 5546-5552; DOI: 10.1158/1078-0432.CCR-10-2616.
• Morrow JK, Lin HK, Sun SC, Zhang S. 2015. Targeting ubiquitination for cancer therapies. Future Med Chem, 7(17): 2333‐2350. DOI: 10.4155/fmc.15.148.
• Nagasaka M, Li Y, Sukari A, Ou S-HI, Al-Hallak MN, Azmi AS. 2020. KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne? Cancer Treat Rev, 84: 101974. DOI: 10.1016/j.ctrv.2020.101974.
• Nitulescu GM, Margina D, Juzenas P, Peng Q, Olaru OT. 2016. Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review). Int J Oncol, 48(3): 869‐885. DOI: 10.3892/ijo.2015.3306.
• Nowell C, Radtke F. 2017. Notch as a tumour suppressor. Nat Rev Cancer, 17(3): 145-159. DOI: 10.1038/nrc.2016.145.
• Park HK, Lee JE, Lim J, Jo DE, Park SA, Suh PG. 2014. Combination treatment with doxorubicin and gamitrinib synergistically augments anticancer activity through enhanced activation of Bim. BMC Cancer, 14: 431. DOI: 10.1186/1471-2407-14-431.
• Parsons SJ, Parsons JT. 2004. Src family kinases, key regulators of signal transduction. Oncogene, 23(48): 7906‐7909. DOI: 10.1038/sj.onc.1208160.
• Paul MK, Mukhopadhyay AK. 2004. Tyrosine kinase – Role and significance in cancer. Int J Med Sci, 1(2): 101-115. DOI: 10.7150/ijms.1.101.
• Pulford K, Morris SW, Turturro F. 2004. Anaplastic lymphoma kinase proteins in growth control and cancer. J Cell Physiol, 199(3): 330‐358. DOI: 10.1002/jcp.10472.
• Rehman G, Shehzad A, Khan AL, Hamayun M. 2014. Role of AMP-activated protein kinase in cancer therapy. Arch Pharm (Weinheim), 347(7): 457‐468. DOI: 10.1002/ardp.201300402.
• Sánchez-Martínez C, Gelbert LM, Lallena MJ, De Dios A. 2015. Cyclin dependent kinase (CDK) inhibitors as anticancer drugs. Bioorg Med Chem Lett, 25(17): 3420-3435. DOI: 10.1016/j.bmcl.2015.05.100.
• Seda V, Mraz M. 2015. B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells. Eur J Haematol, 94(3): 193‐205. DOI: 10.1111/ejh.12427.
• Seshacharyulu P, Ponnusamy MP, Haridas D, Jain M, Ganti AK, Batra SK. 2012. Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets, 16(1): 15‐31. DOI: 10.1517/14728222.2011.648617.
• Siegelin MD. 2013. Inhibition of the mitochondrial Hsp90 chaperone network: A novel, efficient treatment strategy for cancer? Cancer Lett, 333(2): 133-146. DOI: 10.1016/j.canlet.2013.01.045.
• Skoda AM, Simovic D, Karin V, Kardum V, Vranic S, Serman L. 2018. The role of the Hedgehog signaling pathway in cancer: A comprehensive review. Bosn J Basic Med Sci, 18(1): 8‐20. DOI: 10.17305/bjbms.2018.2756.
• Solomon B, Wilner KD, Shaw AT. 2014. Current status of targeted therapy for anaplastic lymphoma kinase-rearranged non-small cell lung cancer. Clin Pharmacol Ther, 95(1): 15‐23. DOI: 10.1038/clpt.2013.200.
• Thomas S, Quinn BA, Das SK, Dash R, Emdad L. 2013. Targeting the Bcl-2 family for cancer therapy. Expert Opin Ther Targets, 17(1): 61‐75. DOI: 10.1517/14728222.2013.733001.
• Touat M, Ileana E, Postel-Vinay S, André F, Soria JC. 2015. Targeting FGFR signaling in cancer. Clin Cancer Res, 21(12): 2684‐2694. DOI: 10.1158/1078-0432.CCR-14-2329.
• Xin P, Xu X, Deng C. 2020. The role of JAK/STAT signaling pathway and its inhibitors in diseases. Int Immunopharmacol, 80: 106210. DOI: 10.1016/j.intimp.2020.106210.
• Yaeger R, Corcoran RB. 2019. Targeting alterations in the RAF–MEK pathway. Cancer Discov, 9(3): 329-341. DOI: 10.1158/2159-8290.CD-18-1321.
• Yip K, Reed J. 2008. Bcl-2 family proteins and cancer. Oncogene, 27: 6398–6406. DOI: 10.1038/onc.2008.307.