EJINME-03344; No of Pages 1

European Journal of Internal Medicine xxx (2016) xxx

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European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Letter to the Editor

Antineoplastic potential of metformin in colorectal cancer KRAS mutation testing permits the selection of individuals (those with
RAS wild-type tumors) who might benefit from agents that target the
Keywords: epidermal growth factor receptor, as cetuximab. It would also be
Metformin interesting to know whether metformin together with conventional
Neoplasms chemotherapy might have a role in treatment of a subgroup of patients
Colorectal neoplasms with colorectal cancer.
Colonic polyps
Diabetes mellitus
KRAS
Conflict of interest

The authors state that they have no conflicts of interest.

Dear Editor,
I read with interest the article “Colon neoplasia in patients with type
2 diabetes on metformin: A meta-analysis” by Rokkas and Portincasa
[1]. As the authors note, the mechanisms underlying the antineoplastic
potential of metformin in colon neoplasia are probably manifold and not
yet completely understood. Experimental data support a direct effect of
metformin in antagonizing specific pathways that promote cell prolifer-
ation, motility, invasion, and migration. As Rokkas and Portincasa
mention, metformin activates AMP-activated protein kinase (AMPK),
leading to downregulation of the mTOR pathway that is crucial to
tumor cell metabolism. I would like to mention another possible
mechanism. In a recent study [2], it was demonstrated that activating
KRAS mutation imposes an embryonic stem cell-like program during
human colon cancer initiation from colon adenoma to stage I carcinoma.
Metformin inhibits KRAS signaling through mislocalization of KRAS from
the plasma membrane to the cytoplasm [3], and, interestingly, in other
studies [3,4], this anti-diabetic agent was most effective against tumors
with activating mutations in KRAS. KRAS mutations are found in 30–50%
of patients with sporadic colorectal cancer [5] and, in clinical practice,
References
[1] Rokkas T, Portincasa P. Colon neoplasia in patients with type 2 diabetes on
metformin: a meta-analysis. Eur J Intern Med 2016;33:60–6.
[2] Le Rolle AF, Chiu TK, Zeng Z, et al. Oncogenic KRAS activates an embryonic stem cell-
like program in human colon cancer initiation. Oncotarget 2016;7:2159–74.
[3] Iglesias DA, Yates MS, van der Hoeven, et al. Another surprise from metformin: novel
mechanism of action via K-ras influences endometrial cancer response to therapy.
Mol Cancer Ther 2013;12:2847–56.
[4] Ma Y, Guo FC, Wang W, Shi HS, Li D, Wang YS. K-ras gene mutation as a predictor of
cancer cell responsiveness to metformin. Mol Med Rep 2013;8:763–8.
[5] Watson R, Liu TC, Ruzinova MB. High frequency of KRAS mutation in early onset
colorectal adenocarcinoma: implications for pathogenesis. Hum Pathol 2016.
http://dx.doi.org/10.1016/j.humpath.2016.06.010.
Francisco José Fernández-Fernández
Department of Internal Medicine, Hospital Arquitecto Marcide,
Complejo Hospitalario Universitario de Ferrol, Ferrol 15405, Spain
E-mail address: fjf.fernandez2@gmail.com.
26 August 2016
Available online xxxx

http://dx.doi.org/10.1016/j.ejim.2016.08.034
0953-6205/© 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Please cite this article as: Fernández-Fernández FJ, Antineoplastic potential of metformin in colorectal cancer, Eur J Intern Med (2016), http://
dx.doi.org/10.1016/j.ejim.2016.08.034