Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2015

Open Access 01-12-2015 | Research

Preclinical analysis of the anti-tumor and anti-metastatic effects of Raf265 on colon cancer cells and CD26+ cancer stem cells in colorectal carcinoma

Authors: Ariel KM Chow, Nathan SM Cheng, Colin SC Lam, Lui Ng, Sunny KM Wong, Timothy MH Wan, Johnny HW Man, Alvin HK Cheung, Thomas CC Yau, Jensen TC Poon, Wai-Lun Law, Roberta WC Pang

Published in: Molecular Cancer | Issue 1/2015

Login to get access

Abstract

Background

In colorectal carcinoma (CRC), activation of the Raf/MEK/ERK signaling pathway is commonly observed. In addition, the commonly used 5FU-based chemotherapy in patients with metastatic CRC was found to enrich a subpopulation of CD26+ cancer stem cells (CSCs). As activation of the Raf/MEK/ERK signaling pathway was also found in the CD26+ CSCs and therefore, we hypothesized that an ATP-competitive pan-Raf inhibitor, Raf265, is effective in eliminating the cancer cells and the CD26+ CSCs in CRC patients.

Methods

HT29 and HCT116 cells were treated with various concentrations of Raf265 to study the anti-proliferative and apoptotic effects of Raf265. Anti-tumor effect was also demonstrated using a xenograft model. Cells were also treated with Raf265 in combination with 5FU to demonstrate the anti-migratory and invasive effects by targeting on the CD26+ CSCs and the anti-metastatic effect of the combined treatment was shown in an orthotopic CRC model.

Results

Raf265 was found to be highly effective in inhibiting cell proliferation and tumor growth through the inhibition of the RAF/MEK/ERK signaling pathway. In addition, anti-migratory and invasive effect was found with Raf265 treatment in combination with 5FU by targeting on the CD26+ cells. Finally, the anti-tumor and anti-metastatic effect of Raf265 in combination with 5FU was also demonstrated.

Conclusions

This preclinical study demonstrates the anti-tumor and anti-metastatic activity of Raf265 in CRC, providing the basis for exploiting its potential use and combination therapy with 5FU in the clinical treatment of CRC.
Literature
1.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. doi:10.3322/caac.20107.PubMedCrossRef
2.
Tomlinson JS, Jarnagin WR, DeMatteo RP, Fong Y, Kornprat P, Gonen M, et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol. 2007;25(29):4575–80. doi:10.1200/JCO.2007.11.0833.PubMedCrossRef
3.
Fong Y, Cohen AM, Fortner JG, Enker WE, Turnbull AD, Coit DG, et al. Liver resection for colorectal metastases. J Clin Oncol. 1997;15(3):938–46.PubMed
4.
Abdalla EK, Vauthey JN, Ellis LM, Ellis V, Pollock R, Broglio KR, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg. 2004;239(6):818–25. discussion 25–7.PubMedCentralPubMedCrossRef
5.
Cascinu S, Berardi R, Salvagni S, Beretta GD, Catalano V, Pucci F, et al. A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression, amplification and NF-kB activation. Br J Cancer. 2008;98(1):71–6. doi:10.1038/sj.bjc.6604121.PubMedCentralPubMedCrossRef
6.
Pang R, Law WL, Chu AC, Poon JT, Lam CS, Chow AK, et al. A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell. 2010;6(6):603–15. doi:10.1016/j.stem.2010.04.001.PubMedCrossRef
7.
Wong KK. Recent developments in anti-cancer agents targeting the Ras/Raf/ MEK/ERK pathway. Recent Pat Anticancer Drug Discov. 2009;4(1):28–35.PubMedCrossRef
8.
Friday BB, Adjei AA. Advances in targeting the Ras/Raf/MEK/Erk mitogen-activated protein kinase cascade with MEK inhibitors for cancer therapy. Clin Cancer Res. 2008;14(2):342–6. doi:10.1158/1078-0432.CCR-07-4790.PubMedCrossRef
9.
10.
Su Y, Vilgelm AE, Kelley MC, Hawkins OE, Liu Y, Boyd KL, et al. RAF265 inhibits the growth of advanced human melanoma tumors. Clin Cancer Res. 2012;18(8):2184–98. doi:10.1158/1078-0432.CCR-11-1122.PubMedCentralPubMedCrossRef
11.
Zitzmann K, de Toni E, von Ruden J, Brand S, Goke B, Laubender RP, et al. The novel Raf inhibitor Raf265 decreases Bcl-2 levels and confers TRAIL-sensitivity to neuroendocrine tumour cells. Endocr Relat Cancer. 2011;18(2):277–85. doi:10.1530/ERC-10-0108.PubMedCrossRef
12.
Spano JP, Fagard R, Soria JC, Rixe O, Khayat D, Milano G. Epidermal growth factor receptor signaling in colorectal cancer: preclinical data and therapeutic perspectives. Ann Oncol. 2005;16(2):189–94. doi:10.1093/annonc/mdi057.PubMedCrossRef
13.
Roth AD, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60–00 trial. J Clin Oncol. 2010;28(3):466–74. doi:10.1200/JCO.2009.23.3452.PubMedCrossRef
14.
Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature. 2002;418(6901):934. doi:10.1038/418934a.PubMedCrossRef
15.
Garnett MJ, Marais R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell. 2004;6(4):313–9. doi:10.1016/j.ccr.2004.09.022.PubMedCrossRef
16.
Safaee Ardekani G, Jafarnejad SM, Tan L, Saeedi A, Li G. The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PLoS One. 2012;7(10):e47054. doi:10.1371/journal.pone.0047054.PubMedCentralPubMedCrossRef
17.
Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene. 2007;26(22):3279–90. doi:10.1038/sj.onc.1210421.PubMedCrossRef
18.
Yokota T, Ura T, Shibata N, Takahari D, Shitara K, Nomura M, et al. BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer. Br J Cancer. 2011;104(5):856–62. doi:10.1038/bjc.2011.19.PubMedCentralPubMedCrossRef
19.
Pai RK, Jayachandran P, Koong AC, Chang DT, Kwok S, Ma L, et al. BRAF-mutated, microsatellite-stable adenocarcinoma of the proximal colon: an aggressive adenocarcinoma with poor survival, mucinous differentiation, and adverse morphologic features. Am J Surg Pathol. 2012;36(5):744–52. doi:10.1097/PAS.0b013e31824430d7.PubMedCrossRef
20.
Laurent-Puig P, Cayre A, Manceau G, Buc E, Bachet JB, Lecomte T, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009;27(35):5924–30. doi:10.1200/JCO.2008.21.6796.PubMedCrossRef
21.
Samowitz WS, Sweeney C, Herrick J, Albertsen H, Levin TR, Murtaugh MA, et al. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res. 2005;65(14):6063–9. doi:10.1158/0008-5472.CAN-05-0404.PubMedCrossRef
22.
Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464(7287):427–30. doi:10.1038/nature08902.PubMedCentralPubMedCrossRef
23.
Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012;2(3):227–35. doi:10.1158/2159-8290.CD-11-0341.PubMedCentralPubMedCrossRef
24.
Mao M, Tian F, Mariadason JM, Tsao CC, Lemos Jr R, Dayyani F, et al. Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents. Clin Cancer Res. 2013;19(3):657–67. doi:10.1158/1078-0432.CCR-11-1446.PubMedCentralPubMedCrossRef
25.
Poulikakos PI, Rosen N. Mutant BRAF melanomas–dependence and resistance. Cancer Cell. 2011;19(1):11–5. doi:10.1016/j.ccr.2011.01.008.PubMedCrossRef
26.
Joseph EW, Pratilas CA, Poulikakos PI, Tadi M, Wang W, Taylor BS, et al. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc Natl Acad Sci U S A. 2010;107(33):14903–8. doi:10.1073/pnas.1008990107.PubMedCentralPubMedCrossRef
27.
Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337–45. doi:10.1056/NEJMoa033025.PubMedCrossRef
28.
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42. doi:10.1056/NEJMoa032691.PubMedCrossRef
29.
Chow AK, Ng L, Sing Li H, Cheng CW, Lam CS, Yau TC, et al. Anti-tumor efficacy of a recombinant human arginase in human hepatocellular carcinoma. Curr Cancer Drug Targets. 2012;12(9):1233–43.PubMed
Metadata
Title
Preclinical analysis of the anti-tumor and anti-metastatic effects of Raf265 on colon cancer cells and CD26+ cancer stem cells in colorectal carcinoma
Authors
Ariel KM Chow
Nathan SM Cheng
Colin SC Lam
Lui Ng
Sunny KM Wong
Timothy MH Wan
Johnny HW Man
Alvin HK Cheung
Thomas CC Yau
Jensen TC Poon
Wai-Lun Law
Roberta WC Pang
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2015
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-015-0352-y

Other articles of this Issue 1/2015

Molecular Cancer 1/2015 Go to the issue

Review

p66Shc as a switch in bringing about contrasting responses in cell growth: implications on cell proliferation and apoptosis

Short communication

Transcriptome sequencing reveals CHD1 as a novel fusion partner of RUNX1 in acute myeloid leukemia with t(5;21)(q21;q22)

Research

Antitumor effects of pharmacological EZH2 inhibition on malignant peripheral nerve sheath tumor through the miR-30a and KPNB1 pathway

Research

Male-specific hepatitis B virus large surface protein variant W4P potentiates tumorigenicity and induces gender disparity

Research

miR-634 restores drug sensitivity in resistant ovarian cancer cells by targeting the Ras-MAPK pathway

Research

AduPARE1A and gemcitabine combined treatment trigger synergistic antitumor effects in pancreatic cancer through NF-κB mediated uPAR activation
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits