Molecular Pathways, Targeted Therapies, and Proteomic
Investigations of Colorectal Cancer

Azmi       Yerlikaya; Sezgin       Zeren
Abstract

According to the GLOBOCAN 2020 data, colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer-related death. The risk factors for colorectal cancer include a diet abundant with fat, refined carbohydrates, animal protein, low fiber content, alcoholism, obesity, long-term cigarette smoking, low physical activity, and aging. Colorectal carcinomas are classified as adenocarcinoma, neuroendocrine, squamous cell, adenosquamous, spindle cell, and undifferentiated carcinomas. In addition, many variants of colorectal carcinomas have been recently distinguished based on histological, immunological, and molecular characteristics. Recently developed targeted molecules in conjunction with standard chemotherapeutics or immune checkpoint inhibitors provide promising treatment protocols for colorectal cancer. However, the benefit of targeted therapies is strictly dependent on the mutational status of signaling molecules (e.g., KRAS) or mismatch repair systems. Here it is aimed to provide a comprehensive view of colorectal cancer types, molecular pathways associated, recently developed targeted therapies, as well as proteomic investigations applied to colorectal cancer for the discovery of novel biomarkers and new targets for treatment protocols.
Keywords: Colorectum, cancer, MSS, MSI, targeted therapies, proteomics.
[1]
Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet  2019; 394(10207): 1467-80.
 [http://dx.doi.org/10.1016/S0140-6736(19)32319-0] [PMID: 31631858]

[2]
Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin  2021; 71(3): 209-49.
 [http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]

[3]
Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin  2020; 70(3): 145-64.
 [http://dx.doi.org/10.3322/caac.21601] [PMID: 32133645]

[4]
Chang JW, Shin DW, Han KD, et al. Obesity has a stronger relationship with colorectal cancer in postmenopausal women than premenopausal women. Cancer Epidemiol Biomarkers Prev  2020; 29(11): 2277-88.
 [http://dx.doi.org/10.1158/1055-9965.EPI-20-0594] [PMID: 32868317]

[5]
Chao A, Thun MJ, Jacobs EJ, Henley SJ, Rodriguez C, Calle EE. Cigarette smoking and colorectal cancer mortality in the cancer prevention study II. J Natl Cancer Inst  2000; 92(23): 1888-96.
 [http://dx.doi.org/10.1093/jnci/92.23.1888] [PMID: 11106680]

[6]
Lin TC, Chien WC, Hu JM, et al. Risk of colorectal cancer in patients with alcoholism: a nationwide, population-based nested case-control study. PLoS One  2020; 15(5): e0232740.
 [http://dx.doi.org/10.1371/journal.pone.0232740] [PMID: 32396577]

[7]
Aparicio T, Ducreux M, Faroux R, et al. for FFCD investigators. Overweight is associated to a better prognosis in metastatic colorectal cancer: a pooled analysis of FFCD trials. Eur J Cancer  2018; 98: 1-9.
 [http://dx.doi.org/10.1016/j.ejca.2018.03.031] [PMID: 29807237]

[8]
Ruddon WR. Cancer Biology. New York Oxford University Press, Inc. 2007.

[9]
Sameer AS. Colorectal cancer: molecular mutations and polymorphisms. Front Oncol  2013; 3: 114.
 [http://dx.doi.org/10.3389/fonc.2013.00114] [PMID: 23717813]

[10]
Fleming M, Ravula S, Tatishchev SF, Wang HL. Colorectal carcinoma: pathologic aspects. J Gastrointest Oncol  2012; 3(3): 153-73.
 [http://dx.doi.org/10.3978/j.issn.2078-6891.2012.030] [PMID: 22943008]

[11]
Remo A, Fassan M, Vanoli A, et al. Morphology and molecular features of rare colorectal carcinoma histotypes. Cancers (Basel)  2019; 11(7): 1036.
 [http://dx.doi.org/10.3390/cancers11071036] [PMID: 31340478]

[12]
Parker TW, Neufeld KL. APC controls Wnt-induced β-catenin destruction complex recruitment in human colonocytes. Sci Rep  2020; 10(1): 2957.
 [http://dx.doi.org/10.1038/s41598-020-59899-z] [PMID: 32076059]

[13]
Baran B, Mert Ozupek N, Yerli Tetik N, Acar E, Bekcioglu O, Baskin Y. difference between left-sided and right-sided colorectal cancer: a focused review of literature. Gastroenterol Res  2018; 11(4): 264-73.
 [http://dx.doi.org/10.14740/gr1062w] [PMID: 30116425]

[14]
Colussi D, Brandi G, Bazzoli F, Ricciardiello L. Molecular pathways involved in colorectal cancer: implications for disease behavior and prevention. Int J Mol Sci  2013; 14(8): 16365-85.
 [http://dx.doi.org/10.3390/ijms140816365] [PMID: 23965959]

[15]
Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell  1990; 61(5): 759-67.
 [http://dx.doi.org/10.1016/0092-8674(90)90186-I] [PMID: 2188735]

[16]
Aberle H, Bauer A, Stappert J, Kispert A, Kemler R. beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J  1997; 16(13): 3797-804.
 [http://dx.doi.org/10.1093/emboj/16.13.3797] [PMID: 9233789]

[17]
Schneikert J, Behrens J. The canonical Wnt signalling pathway and its APC partner in colon cancer development. Gut  2007; 56(3): 417-25.
 [http://dx.doi.org/10.1136/gut.2006.093310] [PMID: 16840506]

[18]
Menter DG, Davis JS, Broom BM, Overman MJ, Morris J, Kopetz S. Back to the colorectal cancer consensus molecular subtype future. Curr Gastroenterol Rep  2019; 21(2): 5.
 [http://dx.doi.org/10.1007/s11894-019-0674-9] [PMID: 30701321]

[19]
Duraturo F, Liccardo R, De Rosa M, Izzo P. Genetics, diagnosis and treatment of Lynch syndrome: old lessons and current challenges. Oncol Lett  2019; 17(3): 3048-54.
 [http://dx.doi.org/10.3892/ol.2019.9945] [PMID: 30867733]

[20]
Peltomäki P. Deficient DNA mismatch repair: A common etiologic factor for colon cancer. Hum Mol Genet  2001; 10(7): 735-40.
 [http://dx.doi.org/10.1093/hmg/10.7.735] [PMID: 11257106]

[21]
Al-Sohaily S, Biankin A, Leong R, Kohonen-Corish M, Warusavitarne J. Molecular pathways in colorectal cancer. J Gastroenterol Hepatol  2012; 27(9): 1423-31.
 [http://dx.doi.org/10.1111/j.1440-1746.2012.07200.x] [PMID: 22694276]

[22]
Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP. CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA  1999; 96(15): 8681-6.
 [http://dx.doi.org/10.1073/pnas.96.15.8681] [PMID: 10411935]

[23]
Liang TJ, Wang HX, Zheng YY, et al. APC hypermethylation for early diagnosis of colorectal cancer: a meta-analysis and literature review. Oncotarget  2017; 8(28): 46468-79.
 [http://dx.doi.org/10.18632/oncotarget.17576] [PMID: 28515349]

[24]
Molnár B, Galamb O, Péterfia B, et al. Gene promoter and exon DNA methylation changes in colon cancer development - mRNA expression and tumor mutation alterations. BMC Cancer  2018; 18(1): 695.
 [http://dx.doi.org/10.1186/s12885-018-4609-x] [PMID: 29945573]

[25]
Psofaki V, Kalogera C, Tzambouras N, et al. Promoter methylation status of hMLH1, MGMT, and CDKN2A/p16 in colorectal adenomas. World J Gastroenterol  2010; 16(28): 3553-60.
 [http://dx.doi.org/10.3748/wjg.v16.i28.3553] [PMID: 20653064]

[26]
Galamb O, Kalmár A, Péterfia B, et al. Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer. Epigenetics  2016; 11(8): 588-602.
 [http://dx.doi.org/10.1080/15592294.2016.1190894] [PMID: 27245242]

[27]
Bosman F, Yan P. Molecular pathology of colorectal cancer. Pol J Pathol  2014; 65(4): 257-66.
 [http://dx.doi.org/10.5114/pjp.2014.48094] [PMID: 25693079]

[28]
Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther  2020; 5(1): 22.
 [http://dx.doi.org/10.1038/s41392-020-0116-z] [PMID: 32296018]

[29]
Min H, Xu M, Chen ZR, et al. Bortezomib induces protective autophagy through AMP-activated protein kinase activation in cultured pancreatic and colorectal cancer cells. Cancer Chemother Pharmacol  2014; 74(1): 167-76.
 [http://dx.doi.org/10.1007/s00280-014-2451-7] [PMID: 24842158]

[30]
Roeten MSF, Cloos J, Jansen G. Positioning of proteasome inhibitors in therapy of solid malignancies. Cancer Chemother Pharmacol  2018; 81(2): 227-43.
 [http://dx.doi.org/10.1007/s00280-017-3489-0] [PMID: 29184971]

[31]
Schmidt S, Denk S, Wiegering A. Targeting protein synthesis in colorectal cancer. Cancers (Basel)  2020; 12(5): 1298.
 [http://dx.doi.org/10.3390/cancers12051298] [PMID: 32455578]

[32]
Xie Q, Liu Y, Li X. The interaction mechanism between autophagy and apoptosis in colon cancer. Transl Oncol  2020; 13(12): 100871.
 [http://dx.doi.org/10.1016/j.tranon.2020.100871] [PMID: 32950931]

[33]
Seow HF, Yip WK, Fifis T. Advances in targeted and immunobased therapies for colorectal cancer in the genomic era. OncoTargets Ther  2016; 9: 1899-920.
 [http://dx.doi.org/10.2147/OTT.S95101] [PMID: 27099521]

[34]
Goldberg RM. Cetuximab. Nat Rev Drug Discov  2005;  (Suppl:)S10-1.
 [http://dx.doi.org/10.1038/nrd1728] [PMID: 15962524]

[35]
Okada Y, Kimura T, Nakagawa T, et al. EGFR downregulation after anti-EGFR therapy predicts the antitumor effect in colorectal cancer. Mol Cancer Res  2017; 15(10): 1445-54.
 [http://dx.doi.org/10.1158/1541-7786.MCR-16-0383] [PMID: 28698359]

[36]
Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med  2009; 360(14): 1408-17.
 [http://dx.doi.org/10.1056/NEJMoa0805019] [PMID: 19339720]

[37]
Caputo F, Santini C, Bardasi C, et al. BRAF-mutated colorectal cancer: clinical and molecular insights. Int J Mol Sci  2019; 20(21): 5369.
 [http://dx.doi.org/10.3390/ijms20215369] [PMID: 31661924]

[38]
Kopetz S, Desai J, Chan E, et al. Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J Clin Oncol  2015; 33(34): 4032-8.
 [http://dx.doi.org/10.1200/JCO.2015.63.2497] [PMID: 26460303]

[39]
Hong DS, Morris VK, El Osta B, et al. Phase IB study of vemurafenib in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with BRAFV600E mutation. Cancer Discov  2016; 6(12): 1352-65.
 [http://dx.doi.org/10.1158/2159-8290.CD-16-0050] [PMID: 27729313]

[40]
Yang H, Higgins B, Kolinsky K, et al. Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer. Cancer Res  2012; 72(3): 779-89.
 [http://dx.doi.org/10.1158/0008-5472.CAN-11-2941] [PMID: 22180495]

[41]
Meric-Bernstam F, Hurwitz H, Raghav KPS, et al. Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol  2019; 20(4): 518-30.
 [http://dx.doi.org/10.1016/S1470-2045(18)30904-5] [PMID: 30857956]

[42]
Seo AN, Kwak Y, Kim DW, et al. HER2 status in colorectal cancer: its clinical significance and the relationship between HER2 gene amplification and expression. PLoS One  2014; 9(5): e98528.
 [http://dx.doi.org/10.1371/journal.pone.0098528] [PMID: 24879338]

[43]
Swain SM, Miles D, Kim SB, et al. CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol  2020; 21(4): 519-30.
 [http://dx.doi.org/10.1016/S1470-2045(19)30863-0] [PMID: 32171426]

[44]
Welch S, Spithoff K, Rumble RB, Maroun J. Bevacizumab combined with chemotherapy for patients with advanced colorectal cancer: a systematic review. Ann Oncol  2010; 21(6): 1152-62.
 [http://dx.doi.org/10.1093/annonc/mdp533] [PMID: 19942597]

[45]
Marques RP, Godinho AR, Heudtlass P, Pais HL, Quintela A, Martins AP. Cetuximab versus bevacizumab in metastatic colorectal cancer: a comparative effectiveness study. J Cancer Res Clin Oncol  2020; 146(5): 1321-34.
 [http://dx.doi.org/10.1007/s00432-020-03167-0] [PMID: 32144533]

[46]
Prasad V, Kaestner V. Nivolumab and pembrolizumab: Monoclonal antibodies against programmed cell death-1 (PD-1) that are interchangeable. Semin Oncol  2017; 44(2): 132-5.
 [http://dx.doi.org/10.1053/j.seminoncol.2017.06.007] [PMID: 28923211]

[47]
Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol  2014; 32(10): 1020-30.
 [http://dx.doi.org/10.1200/JCO.2013.53.0105] [PMID: 24590637]

[48]
Guo L, Zhang H, Chen B. Nivolumab as programmed death-1 (PD-1) inhibitor for targeted immunotherapy in tumor. J Cancer  2017; 8(3): 410-6.
 [http://dx.doi.org/10.7150/jca.17144] [PMID: 28261342]

[49]
Savoia P, Astrua C, Fava P. Ipilimumab (Anti-Ctla-4 Mab) in the treatment of metastatic melanoma: effectiveness and toxicity management. Hum Vaccin Immunother  2016; 12(5): 1092-101.
 [http://dx.doi.org/10.1080/21645515.2015.1129478] [PMID: 26889818]

[50]
Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol  2017; 18(9): 1182-91.
 [http://dx.doi.org/10.1016/S1470-2045(17)30422-9] [PMID: 28734759]

[51]
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med  2015; 372(26): 2509-20.
 [http://dx.doi.org/10.1056/NEJMoa1500596] [PMID: 26028255]

[52]
Petrova D, Toncheva D. Proteomic techniques in colorectal cancer research. Biotechnol Biotechnol Equip  2008; 22(2): 660-3.
 [http://dx.doi.org/10.1080/13102818.2008.10817531]

[53]
Zhang B, Pan X, Cobb GP, Anderson TA. microRNAs as oncogenes and tumor suppressors. Dev Biol  2007; 302(1): 1-12.
 [http://dx.doi.org/10.1016/j.ydbio.2006.08.028] [PMID: 16989803]

[54]
Okur E, Yerlikaya A. A novel and effective inhibitor combination involving bortezomib and OTSSP167 for breast cancer cells in light of label-free proteomic analysis. Cell Biol Toxicol  2019; 35(1): 33-47.
 [http://dx.doi.org/10.1007/s10565-018-9435-z] [PMID: 29948483]

[55]
Yerlikaya A, Okur E, Baykal AT, Acılan C, Boyacı I, Ulukaya E. A proteomic analysis of p53-independent induction of apoptosis by bortezomib in 4T1 breast cancer cell line. J Proteomics  2015; 113: 315-25.
 [http://dx.doi.org/10.1016/j.jprot.2014.09.010] [PMID: 25305590]

[56]
Le KPU, Vo PU, Le KM, et al. 2D-Page analysis of Vietnamese colorectal cancer tissue samples. 6th International Conference on the Development of Biomedical Engineering in Vietnam (BME6).  In: Springer; Singapore. 2018; pp. 287-93.
 [http://dx.doi.org/10.1007/978-981-10-4361-1_48]

[57]
Lim LC, Looi ML, Zakaria SZ, et al. Identification of differentially expressed proteins in the serum of colorectal cancer patients using 2D-DIGE proteomics analysis. Pathol Oncol Res  2016; 22(1): 169-77.
 [http://dx.doi.org/10.1007/s12253-015-9991-y] [PMID: 26463353]

[58]
de Noo ME, Mertens BJ, Ozalp A, et al. Detection of colorectal cancer using MALDI-TOF serum protein profiling. Eur J Cancer  2006; 42(8): 1068-76.
 [http://dx.doi.org/10.1016/j.ejca.2005.12.023] [PMID: 16603345]

[59]
Wang H, Luo C, Zhu S, et al. Serum peptidome profiling for the diagnosis of colorectal cancer: discovery and validation in two independent cohorts. Oncotarget  2017; 8(35): 59376-86.
 [http://dx.doi.org/10.18632/oncotarget.19587] [PMID: 28938643]

[60]
Aggarwal S, Yadav AK. Dissecting the iTRAQ data analysis. Methods Mol Biol  2016; 1362: 277-91.
 [http://dx.doi.org/10.1007/978-1-4939-3106-4_18] [PMID: 26519184]

[61]
Liu G, Fei F, Qu J, et al. iTRAQ-based proteomic analysis of DMH-induced colorectal cancer in mice reveals the expressions of β-catenin, decorin, septin-7, and S100A10 expression in 53 cases of human hereditary polyposis colorectal cancer. Clin Transl Oncol  2019; 21(2): 220-31.
 [http://dx.doi.org/10.1007/s12094-018-1912-6] [PMID: 29956073]

[62]
Lin Q, Tan HT, Lim TK, Khoo A, Lim KH, Chung MC. iTRAQ analysis of colorectal cancer cell lines suggests Drebrin (DBN1) is overexpressed during liver metastasis. Proteomics  2014; 14(11): 1434-43.
 [http://dx.doi.org/10.1002/pmic.201300462] [PMID: 24610677]

[63]
Lundgren DH, Hwang SI, Wu L, Han DK. Role of spectral counting in quantitative proteomics. Expert Rev Proteomics  2010; 7(1): 39-53.
 [http://dx.doi.org/10.1586/epr.09.69] [PMID: 20121475]

[64]
Bauer KM, Lambert PA, Hummon AB. Comparative label-free LC-MS/MS analysis of colorectal adenocarcinoma and metastatic cells treated with 5-fluorouracil. Proteomics  2012; 12(12): 1928-37.
 [http://dx.doi.org/10.1002/pmic.201200041] [PMID: 22623418]

[65]
Cantor DI, Cheruku HR, Westacott J, Shin JS, Mohamedali A, Ahn SB. Proteomic investigations into resistance in colorectal cancer. Expert Rev Proteomics  2020; 17(1): 49-65.
 [http://dx.doi.org/10.1080/14789450.2020.1713103] [PMID: 31914823]

[66]
Yu J, Zhai X, Li X, et al. Identification of MST1 as a potential early detection biomarker for colorectal cancer through a proteomic approach. Sci Rep  2017; 7(1): 14265.
 [http://dx.doi.org/10.1038/s41598-017-14539-x] [PMID: 29079854]

[67]
O’Dwyer D, Ralton LD, O’Shea A, Murray GI. The proteomics of colorectal cancer: identification of a protein signature associated with prognosis. PLoS One  2011; 6(11): e27718.
 [http://dx.doi.org/10.1371/journal.pone.0027718] [PMID: 22125622]

[68]
Lièvre A, Blons H, Laurent-Puig P. Oncogenic mutations as predictive factors in colorectal cancer. Oncogene  2010; 29(21): 3033-43.
 [http://dx.doi.org/10.1038/onc.2010.89] [PMID: 20383189]

[69]
Kwong LN, Dove WF. APC and its modifiers in colon cancer. Adv Exp Med Biol  2009; 656: 85-106.
 [http://dx.doi.org/10.1007/978-1-4419-1145-2_8] [PMID: 19928355]

[70]
Baghban R, Roshangar L, Jahanban-Esfahlan R, et al. Tumor microenvironment complexity and therapeutic implications at a glance. Cell Commun Signal  2020; 18(1): 59.
 [http://dx.doi.org/10.1186/s12964-020-0530-4] [PMID: 32264958]

[71]
Han SW, Kim HP, Shin JY, et al. Targeted sequencing of cancer-related genes in colorectal cancer using next-generation sequencing. PLoS One  2013; 8(5): e64271.
 [http://dx.doi.org/10.1371/journal.pone.0064271] [PMID: 23700467]

[72]
Reynolds NA, Wagstaff AJ. Cetuximab: in the treatment of metastatic colorectal cancer. Drugs  2004; 64(1): 109-18.
 [http://dx.doi.org/10.2165/00003495-200464010-00007] [PMID: 14723561]

[73]
Messersmith WA, Hidalgo M. Panitumumab, a monoclonal anti epidermal growth factor receptor antibody in colorectal cancer: Another one or the one? Clin Cancer Res  2007; 13(16): 4664-6.
 [http://dx.doi.org/10.1158/1078-0432.CCR-07-0065] [PMID: 17699842]

[74]
Abraham J, Stenger M. Dabrafenib in advanced melanoma with BRAF V600E mutation. J Community Support Oncol  2014; 12(2): 48-9.
 [http://dx.doi.org/10.12788/jcso.0014] [PMID: 24971404]

[75]
Corcoran RB, Atreya CE, Falchook GS, et al. Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer. J Clin Oncol  2015; 33(34): 4023-31.
 [http://dx.doi.org/10.1200/JCO.2015.63.2471] [PMID: 26392102]

[76]
Cotto-Rios XM, Agianian B, Gitego N, et al. Inhibitors of BRAF dimers using an allosteric site. Nat Commun  2020; 11(1): 4370.
 [http://dx.doi.org/10.1038/s41467-020-18123-2] [PMID: 32873792]

[77]
Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-Mutated colorectal cancer. N Engl J Med  2019; 381(17): 1632-43.
 [http://dx.doi.org/10.1056/NEJMoa1908075] [PMID: 31566309]

[78]
Cao D, Zheng Y, Xu H, Ge W, Xu X. Bevacizumab improves survival in metastatic colorectal cancer patients with primary tumor resection: a meta-analysis. Sci Rep  2019; 9(1): 20326.
 [http://dx.doi.org/10.1038/s41598-019-56528-2] [PMID: 31889159]

[79]
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med  2004; 350(23): 2335-42.
 [http://dx.doi.org/10.1056/NEJMoa032691] [PMID: 15175435]

[80]
Dhillon S. Regorafenib: a review in metastatic colorectal cancer. Drugs  2018; 78(11): 1133-44.
 [http://dx.doi.org/10.1007/s40265-018-0938-y] [PMID: 29943375]

[81]
Jung G, Benítez-Ribas D, Sánchez A, Balaguer F. Current treatments of metastatic colorectal cancer with immune checkpoint inhibitors-2020 update. J Clin Med  2020; 9(11): 3520.
 [http://dx.doi.org/10.3390/jcm9113520] [PMID: 3314268]
Cite As
Current Molecular Medicine

Molecular Pathways, Targeted Therapies, and Proteomic Investigations of Colorectal Cancer

Abstract
