The Effective Role of Targeted Therapy in Advanced Colorectal Cancer


  • Sarah K. Obay Department of Pharmacology and Toxicology / College of Pharmacy/ Kufa University
  • Ali N. Wannas Department of Pharmaceutics / College of Pharmacy/ Kufa University
  • Rana A. Ghaleb Department of Anatomy and Histology/College of Medicine/ University of Babylon



colorectal cancer (CRC), metastatic, chemotherapy, targeting drug


Though chemotherapy is the major strategy to manage patients with advanced-stage colorectal cancer (CRC), the main challenge is the progression of CRC despite using combination of different chemotherapeutic agents. So, to overcome this challenge, a new class

Of therapy was developed naming “Targeted-therapy”. This class of drugs aim to target specific overexpressed or aberrant enzyme, receptor, or gene that have critical role in the growth and survival of colorectal cancerous cells. So that, by using combination of traditional strategy (chemotherapy) and targeted-drug, this will lead to improve survival and prevent the progression of advanced CRC


- World Health Organization (WHO) and the International Agency for Research on Cancer (IARC). Iraqi Cancer incidence and mortality. Iraq - Glob Cancer Obs Globocan 2020. 2020;2020–1.

- Jung G, Hernández-Illán E, Moreira L, Balaguer F, Goel A. Epigenetics of colorectal cancer: biomarker and therapeutic potential. Nat Rev Gastroenterol Hepatol. 2020;17(2):111–30.

- Wu C. Systemic Therapy for Colon Cancer. Surg Oncol Clin N Am. 2018;27(2):235–42. Available from:

- Lupinacci RM, Andraus W, De Paiva Haddad LB, Carneiro D′Albuquerque LA, Herman P. Simultaneous laparoscopic resection of primary colorectal cancer and associated liver metastases: A systematic review. Tech Coloproctol. 2014;18(2):129–35.

- van der Geest LGM, Lam-Boer J, Koopman M, Verhoef C, Elferink MAG, de Wilt JHW. Nationwide trends in incidence, treatment and survival of colorectal cancer patients with synchronous metastases. Clin Exp Metastasis. 2015;32(5):457–65.

- Messersmith WA. NCCN Guidelines Updates: Management of Metastatic Colorectal Cancer. J Natl Compr Canc Netw. 2019;17(55):599–601.

- Brown KGM, Solomon MJ, Mahon K, O’Shannassy S. Management of colorectal cancer. BMJ [Internet]. 2019;366(August):1–7.

- Tauriello DVF, Calon A, Lonardo E, Batlle E. Determinants of metastatic competency in colorectal cancer. Mol Oncol. 2017;11(1):97–119.

- Nguyen HT, Duong HQ. The molecular characteristics of colorectal cancer: Implications for diagnosis and therapy (review). Oncol Lett. 2018;16(1):9–18.

- McQuade RM, Stojanovska V, Bornstein JC, Nurgali K. Colorectal Cancer Chemotherapy: The Evolution of Treatment and New Approaches. Curr Med Chem. 2017;24(15):1537–57.

- Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007;370(9582):143–52.

- Goldberg RM. Advances in the Treatment of Metastatic Colorectal Cancer. Oncologist. 2005;10(S3):40–8.

- Van Der Jeught K, Xu HC, Li YJ, Lu X Bin, Ji G. Drug resistance and new therapies in colorectal cancer. World J Gastroenterol. 2018;24(34):3834–48.

- Price TJ, Tang M, Gibbs P, Haller DG, Peeters M, Arnold D, et al. Targeted therapy for metastatic colorectal cancer. Expert Rev Anticancer Ther. 2018;18(10):991–1006.

- Ohhara Y, Fukuda N, Takeuchi S, Honma R, Shimizu Y, Kinoshita I, et al. Role of targeted therapy in metastatic colorectal cancer. World J Gastrointest Oncol. 2016;8(9):642.

- Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther. 2020;5(1).

- Lugano R, Ramachandran M, Dimberg A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci. 2020;77(9):1745–70.

- Riechelmann R, Grothey A. Antiangiogenic therapy for refractory colorectal cancer: Current options and future strategies. Ther Adv Med Oncol. 2017;9(2):106–26.

- Rosen LS, Jacobs IA, Burkes RL. Bevacizumab in Colorectal Cancer: Current Role in Treatment and the Potential of Biosimilars. Target Oncol. 2017;12(5):599–610.

- Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, et al. new england journal. 2004;2335–42.

- Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25(12):1539–44.

- Clarke JM, Hurwitz HI. Targeted therapies: Ziv-aflibercept: Binding to more than VEGF-A-does more matter? Nat Rev Clin Oncol. 2013;10(1):10–1.

- Piawah S, Venook AP. Targeted therapy for colorectal cancer metastases: A review of current methods of molecularly targeted therapy and the use of tumor biomarkers in the treatment of metastatic colorectal cancer. Cancer. 2019;125(23):4139–47.

- Chan DLH, Segelov E, Wong RSH, Smith A, Herbertson RA, Li BT, et al. Epidermal growth factor receptor (EGFR) inhibitors for metastatic colorectal cancer. Cochrane Database Syst Rev. 2017;2017(6).

- Cecchi F, Rabe DC, Bottaro DP. Targeting the HGF/Met signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16(6):553–72.

- Guardiola S, Varese M, Sánchez-Navarro M, Giralt E. A Third Shot at EGFR: New Opportunities in Cancer Therapy. Trends Pharmacol Sci. 2019;40(12):941–55.

- Qin S, Li J, Wang L, Xu J, Cheng Y, Bai Y, et al. Efficacy and tolerability of first-line cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX-4) versus FOLFOX-4 in patientswith RASwild-typemetastatic colorectal cancer: The open-label, randomized, phase III TAILOR trial. J Clin Oncol. 2018;36(30):3031–9.

- Köhne CH, Hofheinz R, Mineur L, Letocha H, Greil R, Thaler J, et al. First-line panitumumab plus irinotecan/5-Xuorouracil/leucovorin treatment in patients with metastatic colorectal cancer. J Cancer Res Clin Oncol. 2012;138(1):65–72.

- Fakih M, Vincent M. Adverse events associated with anti-EGFR therapies for the treatment of metastatic colorectal cancer. Curr Oncol. 2010;17 Suppl 1: S18-30.

- Edwards MS, Chadda SD, Zhao Z, Barber BL, Sykes DP. A systematic review of treatment guidelines for metastatic colorectal cancer. Color Dis. 2012;14(2):31–47.

- Khan M, Maryam A, Qazi JI, Ma T. Targeting apoptosis and multiple signaling pathways with icariside II in cancer cells. International journal of biological sciences. 2015;11(9):1100.

- Amikura K, Akagi K, Ogura T, Takahashi A, Sakamoto H. The RAS mutation status predicts survival in patients undergoing hepatic resection for colorectal liver metastases: The results from a genetic analysis of all-RAS. J Surg Oncol. 2018;117(4):745–55.

- Ducreux M, Chamseddine A, Laurent-Puig P, Smolenschi C, Hollebecque A, Dartigues P, et al. Molecular targeted therapy of BRAF-mutant colorectal cancer. Ther Adv Med Oncol. 2019;11:1–15.

- Messersmith WA. Systemic Management of Colorectal Cancer. JNCCN J Natl Compr Cancer Netw. 2017;15(5S):699–702.

- Nakayama I, Hirota T, Shinozaki E. BRAF mutation in colorectal cancers: From prognostic marker to targetable mutation. Cancers (Basel). 2020;12(11):1–29.

- Turski ML, Vidwans SJ, Janku F, Garrido-Laguna I, Munoz J, Schwab R, et al. Genomically driven tumors and actionability across histologies: BRAF-mutant cancers as a paradigm. Mol Cancer Ther. 2016;15(4):533–47.

- Zhao B, Wang L, Qiu H, Zhang M, Sun L, Peng P, et al. Mechanisms of resistance to anti-EGFR therapy in colorectal cancer. Oncotarget. 2017;8(3):3980–4000.

- Ursem C, Atreya CE, Van Loon K. Emerging treatment options for BRAF-mutant colorectal cancer. Gastrointest Cancer Targets Ther. 2018; Volume 8:13–23.

- Hsu JL, Hung MC. The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer. Cancer Metastasis Rev. 2016;35(4):575–88.

- Ghatak S, Lin K, Lou E, Nelson AC. Trastuzumab-Pertuzumab resistance in a case of HER2-del16 expressing colorectal cancer—a case report. Precis Cancer Med. 2020; 3:21–21.

- Müller V, Clemens M, Jassem J, Al-Sakaff N, Auclair P, Nüesch E, et al. Long-term trastuzumab (Herceptin®) treatment in a continuation study of patients with HER2-positive breast cancer or HER2-positive gastric cancer. BMC Cancer. 2018;18(1):2–7.

- Hainsworth JD, Meric-Bernstam F, Swanton C, Hurwitz H, Spigel DR, Sweeney C, et al. Targeted therapy for advanced solid tumors on the basis of molecular profiles: Results from mypathway, an open-label, phase IIA multiple basket study. J Clin Oncol. 2018;36(6):536–42.

- Sartore-Bianchi A, Trusolino L, Martino C, Bencardino K, Lonardi S, Bergamo F, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17(6):738–46.

- Parcesepe P, Giordano G, Laudanna C, Febbraro A, Pancione M. Cancer-Associated Immune Resistance and Evasion of Immune Surveillance in Colorectal Cancer. Gastroenterol Res Pract. 2016;2016.

- Barriga V, Kuol N, Nurgali K, Apostolopoulos V. The complex interaction between the tumor micro-environment and immune checkpoints in breast cancer. Cancers (Basel). 2019;11(8).

- Salmaninejad A, Valilou SF, Shabgah AG, Aslani S, Alimardani M, Pasdar A, et al. PD-1/PD-L1 pathway: Basic biology and role in cancer immunotherapy. J Cell Physiol. 2019;234(10):16824–37.

- Thomas J, Leal A, Overman MJ. Clinical Development of Immunotherapy for Deficient Mismatch Repair Colorectal Cancer. Clin Colorectal Cancer. 2020;19(2):73–81.

- Fessas P, Lee H, Ikemizu S, Janowitz T. A molecular and preclinical comparison of the PD-1–targeted T-cell checkpoint inhibitors nivolumab and pembrolizumab. Semin Oncol. 2017;44(2):136–40.

- Jazirehi AR, Lim A, Dinh T. PD-1 inhibition and treatment of advanced melanoma-role of pembrolizumab. Am J Cancer Res. 2016;6(10):2117–28.

- Sarshekeh AM, Overman MJ, Kopetz S. Nivolumab in the treatment of microsatellite instability high metastatic colorectal cancer. Futur Oncol. 2018;14(18):1869–74.

- Almutairi AR, McBride A, Slack M, Erstad BL, Abraham I. Potential Immune-Related Adverse Events Associated with Monotherapy and Combination Therapy of Ipilimumab, Nivolumab, and Pembrolizumab for Advanced Melanoma: A Systematic Review and Meta-Analysis. Front Oncol. 2020;10(February):1–31.