Gene Polymorphisms in the CCL5/CCR5 Pathway As a Genetic Biomarker for Outcome and Hand-Foot Skin Reaction in Metastatic Colorectal Cancer Patients Treated With Regorafenib

Overview

Journal Clin Colorectal Cancer

Publisher Elsevier

Specialties Gastroenterology
Oncology

Date 2018 Apr 3

PMID 29606345

Citations 18

Authors

Mitsukuni Suenaga

Marta Schirripa

Shu Cao

Wu Zhang

Dongyun Yang

Yan Ning

Chiara Cremolini

Carlotta Antoniotti

Beatrice Borelli

Tetsuo Mashima

Satoshi Okazaki

Martin D Berger

Yuji Miyamoto

Roel Gopez Jr

Afsaneh Barzi

Sara Lonardi

Toshiharu Yamaguchi

Alfredo Falcone

Fotios Loupakis

Heinz-Josef Lenz

Affiliations

Soon will be listed here.

Abstract

Background: The C-C motif chemokine ligand 5/C-C motif chemokine receptor 5 (CCL5/CCR5) pathway has been shown to induce endothelial progenitor cell migration, resulting in increased vascular endothelial growth factor A expression. We hypothesized that genetic polymorphisms in the CCL5/CCR5 pathway predict efficacy and toxicity in patients with metastatic colorectal cancer (mCRC) treated with regorafenib.

Patients And Methods: We analyzed genomic DNA extracted from 229 tumor samples from 2 different cohorts of patients who received regorafenib: an evaluation cohort of 79 Japanese patients and a validation cohort of 150 Italian patients. Single nucleotide polymorphisms of CCL5/CCR5 pathway-related genes were analyzed by PCR-based direct sequencing.

Results: CCL4 rs1634517 and CCL3 rs1130371 were associated with progression-free survival in the evaluation cohort (hazard ratio [HR] 1.54, P = .043; HR 1.48, P = .064), and progression-free survival (HR 1.74, P < .001; HR 1.66, P = .002) and overall survival (HR 1.65, P = .004; HR 1.65, P = .004) in the validation cohort. The allelic frequencies of CCL5 single nucleotide polymorphisms varied between the evaluation and validation cohorts (G/G variant in rs2280789, 21.5% vs. 1.3%, P < .001; T/T variant in rs3817655, 22.8% vs. 2.7%, P < .001). In the evaluation cohort, patients with the G/G variant in rs2280789 had a higher incidence of grade 3+ hand-foot skin reaction compared to any A allele (53% vs. 27%, P = .078), and similarly to the T/T variant in rs3817655 compared to any A allele (56% vs. 26%, P = .026).

Conclusion: Genetic variants in the CCL5/CCR5 pathway may serve as prognostic markers and may predict severe hand-foot skin reaction in mCRC patients receiving regorafenib therapy.

Citing Articles

Exploratory Study Identifies Matrix Metalloproteinase-14 and -9 as Potential Biomarkers of Regorafenib Efficacy in Metastatic Colorectal Cancer.

Suenaga M, Mashima T, Kawata N, Dan S, Seimiya H, Yamaguchi K Cancers (Basel). 2024; 16(16).

PMID: 39199626 PMC: 11352555. DOI: 10.3390/cancers16162855.

Exploring Predictive and Prognostic Biomarkers in Colorectal Cancer: A Comprehensive Review.

Ashouri K, Wong A, Mittal P, Torres-Gonzalez L, Lo J, Soni S Cancers (Basel). 2024; 16(16).

PMID: 39199569 PMC: 11353018. DOI: 10.3390/cancers16162796.

Association of VEGFA and CCL4L2 polymorphisms with hand-foot skin reaction and survival of regorafenib in Japanese patients with colorectal cancer.

Ono K, Murase R, Matsumoto N, Kubota Y, Ishida H, Fujita K Cancer Chemother Pharmacol. 2024; 94(1):57-66.

PMID: 38459188 DOI: 10.1007/s00280-024-04649-5.

and gene expression in colorectal cancer: comprehensive profiling and clinical value.

Battaglin F, Baca Y, Millstein J, Yang Y, Xiu J, Arai H J Immunother Cancer. 2024; 12(1).

PMID: 38212126 PMC: 10806545. DOI: 10.1136/jitc-2023-007939.

Associations between Single Nucleotide Polymorphisms from the Genes of Chemokines and the CXCR2 Chemokine Receptor and an Increased Risk of Endometrial Cancer.

Wujcicka W, Zajac A, Szyllo K, Romanowicz H, Smolarz B, Stachowiak G Cancers (Basel). 2023; 15(22).

PMID: 38001676 PMC: 10670474. DOI: 10.3390/cancers15225416.

References

Yoshino T, Komatsu Y, Yamada Y, Yamazaki K, Tsuji A, Ura T . Randomized phase III trial of regorafenib in metastatic colorectal cancer: analysis of the CORRECT Japanese and non-Japanese subpopulations. Invest New Drugs. 2014; 33(3):740-50. PMC: 4434855. DOI: 10.1007/s10637-014-0154-x. View

Zhang Y, Lv D, Kim H, Kurt R, Bu W, Li Y . A novel role of hematopoietic CCL5 in promoting triple-negative mammary tumor progression by regulating generation of myeloid-derived suppressor cells. Cell Res. 2012; 23(3):394-408. PMC: 3587709. DOI: 10.1038/cr.2012.178. View

Takahashi H, Hattori S, Iwamatsu A, Takizawa H, Shibuya M . A novel snake venom vascular endothelial growth factor (VEGF) predominantly induces vascular permeability through preferential signaling via VEGF receptor-1. J Biol Chem. 2004; 279(44):46304-14. DOI: 10.1074/jbc.M403687200. View

Wilhelm S, Dumas J, Adnane L, Lynch M, Carter C, Schutz G . Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2010; 129(1):245-55. DOI: 10.1002/ijc.25864. View

Tabernero J, Lenz H, Siena S, Sobrero A, Falcone A, Ychou M . Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial. Lancet Oncol. 2015; 16(8):937-48. PMC: 7513622. DOI: 10.1016/S1470-2045(15)00138-2. View

Musha H, Ohtani H, Mizoi T, Kinouchi M, Nakayama T, Shiiba K . Selective infiltration of CCR5(+)CXCR3(+) T lymphocytes in human colorectal carcinoma. Int J Cancer. 2005; 116(6):949-56. DOI: 10.1002/ijc.21135. View

Lacouture M, Reilly L, Gerami P, Guitart J . Hand foot skin reaction in cancer patients treated with the multikinase inhibitors sorafenib and sunitinib. Ann Oncol. 2008; 19(11):1955-61. DOI: 10.1093/annonc/mdn389. View

An P, Nelson G, Wang L, Donfield S, Goedert J, Phair J . Modulating influence on HIV/AIDS by interacting RANTES gene variants. Proc Natl Acad Sci U S A. 2002; 99(15):10002-7. PMC: 126614. DOI: 10.1073/pnas.142313799. View

Mross K, Frost A, Steinbild S, Hedbom S, Buchert M, Fasol U . A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res. 2012; 18(9):2658-67. DOI: 10.1158/1078-0432.CCR-11-1900. View

10.

Song A, Patel A, Thamatrakoln K, Liu C, Feng D, Clayberger C . Functional domains and DNA-binding sequences of RFLAT-1/KLF13, a Krüppel-like transcription factor of activated T lymphocytes. J Biol Chem. 2002; 277(33):30055-65. DOI: 10.1074/jbc.M204278200. View

11.

Song A, Nikolcheva T, Krensky A . Transcriptional regulation of RANTES expression in T lymphocytes. Immunol Rev. 2001; 177:236-45. DOI: 10.1034/j.1600-065x.2000.17610.x. View

12.

Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M . Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2012; 381(9863):303-12. DOI: 10.1016/S0140-6736(12)61900-X. View

13.

Ishida Y, Kimura A, Kuninaka Y, Inui M, Matsushima K, Mukaida N . Pivotal role of the CCL5/CCR5 interaction for recruitment of endothelial progenitor cells in mouse wound healing. J Clin Invest. 2012; 122(2):711-21. PMC: 3266771. DOI: 10.1172/JCI43027. View

14.

Carmeliet P, Jain R . Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011; 473(7347):298-307. PMC: 4049445. DOI: 10.1038/nature10144. View

15.

Hudson N, Powner M, Sarker M, Burgoyne T, Campbell M, Ockrim Z . Differential apicobasal VEGF signaling at vascular blood-neural barriers. Dev Cell. 2014; 30(5):541-52. PMC: 4160345. DOI: 10.1016/j.devcel.2014.06.027. View

16.

Liu G, Huang Y, Tzeng H, Tsai C, Wang S, Tang C . CCL5 promotes vascular endothelial growth factor expression and induces angiogenesis by down-regulating miR-199a in human chondrosarcoma cells. Cancer Lett. 2014; 357(2):476-87. DOI: 10.1016/j.canlet.2014.11.015. View

17.

Li J, Qin S, Xu R, Yau T, Ma B, Pan H . Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015; 16(6):619-29. DOI: 10.1016/S1470-2045(15)70156-7. View

18.

Balkwill F . Cancer and the chemokine network. Nat Rev Cancer. 2004; 4(7):540-50. DOI: 10.1038/nrc1388. View

19.

Wang S, Liu S, Sun H, Huang T, Chan C, Yang C . CCL5/CCR5 axis induces vascular endothelial growth factor-mediated tumor angiogenesis in human osteosarcoma microenvironment. Carcinogenesis. 2014; 36(1):104-14. DOI: 10.1093/carcin/bgu218. View

20.

Suenaga M, Mashima T, Kawata N, Wakatsuki T, Horiike Y, Matsusaka S . Serum VEGF-A and CCL5 levels as candidate biomarkers for efficacy and toxicity of regorafenib in patients with metastatic colorectal cancer. Oncotarget. 2016; 7(23):34811-23. PMC: 5085191. DOI: 10.18632/oncotarget.9187. View