Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status

Targeted molecular therapy is an effective anticancer strategy. Anti‐EGFR monoclonal antibodies such as cetuximab (CTX) have been approved for the treatment of various malignancies, including colorectal cancer (CRC) with wild‐type KRAS. However, their efficacy in patients with KRAS mutations has not...

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Main Authors:	Kato, Junko, Futamura, Manabu, Kanematsu, Masako, Gaowa, Siqin, Mori, Ryutaro, Tanahashi, Toshiyuki, Matsuhashi, Nobuhisa, Yoshida, Kazuhiro
Format:	Online
Language:	English
Published:	John Wiley and Sons Inc. 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5057332/

id	pubmed-5057332
recordtype	oai_dc
spelling	pubmed-50573322016-10-19 Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status Kato, Junko Futamura, Manabu Kanematsu, Masako Gaowa, Siqin Mori, Ryutaro Tanahashi, Toshiyuki Matsuhashi, Nobuhisa Yoshida, Kazuhiro Cancer Therapy and Prevention Targeted molecular therapy is an effective anticancer strategy. Anti‐EGFR monoclonal antibodies such as cetuximab (CTX) have been approved for the treatment of various malignancies, including colorectal cancer (CRC) with wild‐type KRAS. However, their efficacy in patients with KRAS mutations has not been established. Therefore, we investigated whether CTX treatment was effective as a single agent or in combination with zoledronic acid (ZOL) in human CRC cell lines with different KRAS status. CRC cell lines SW48 (wild‐type KRAS) and LS174T (mutant KRAS) were treated with ZOL, CTX and a combination of both drugs. Cytotoxicity was measured using the MTT assay. Changes in the levels of intracellular signaling proteins were evaluated using western blot analysis. Finally, we evaluated the efficacy of the combination treatment in an in vivo xenograft model. We observed that ZOL apparently inhibited growth in both cell lines, whereas CTX showed little effect. ZOL also increased the levels of unprenylated RAS. Combined ZOL and CTX treatment was synergistic in both cell lines and was associated with inhibition of the RAS‐MAPK and AKT‐mTOR signaling pathways. Furthermore, the combination treatment was more effective in suppressing the growth of xenografts derived from both SW48 and LS174T cells; this effect was associated with increased apoptosis. These results demonstrate that ZOL inhibits the growth of colon cancer cells regardless of KRAS status, and combination therapy using ZOL and CTX enhances this growth suppression. These findings suggest a novel strategy for the treatment of CRC independent of KRAS mutational status. John Wiley and Sons Inc. 2016-03-15 2015-10-23 /pmc/articles/PMC5057332/ /pubmed/26437179 http://dx.doi.org/10.1002/ijc.29881 Text en © 2015 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Kato, Junko Futamura, Manabu Kanematsu, Masako Gaowa, Siqin Mori, Ryutaro Tanahashi, Toshiyuki Matsuhashi, Nobuhisa Yoshida, Kazuhiro
spellingShingle	Kato, Junko Futamura, Manabu Kanematsu, Masako Gaowa, Siqin Mori, Ryutaro Tanahashi, Toshiyuki Matsuhashi, Nobuhisa Yoshida, Kazuhiro Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status
author_facet	Kato, Junko Futamura, Manabu Kanematsu, Masako Gaowa, Siqin Mori, Ryutaro Tanahashi, Toshiyuki Matsuhashi, Nobuhisa Yoshida, Kazuhiro
author_sort	Kato, Junko
title	Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status
title_short	Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status
title_full	Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status
title_fullStr	Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status
title_full_unstemmed	Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status
title_sort	combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of kras status
description	Targeted molecular therapy is an effective anticancer strategy. Anti‐EGFR monoclonal antibodies such as cetuximab (CTX) have been approved for the treatment of various malignancies, including colorectal cancer (CRC) with wild‐type KRAS. However, their efficacy in patients with KRAS mutations has not been established. Therefore, we investigated whether CTX treatment was effective as a single agent or in combination with zoledronic acid (ZOL) in human CRC cell lines with different KRAS status. CRC cell lines SW48 (wild‐type KRAS) and LS174T (mutant KRAS) were treated with ZOL, CTX and a combination of both drugs. Cytotoxicity was measured using the MTT assay. Changes in the levels of intracellular signaling proteins were evaluated using western blot analysis. Finally, we evaluated the efficacy of the combination treatment in an in vivo xenograft model. We observed that ZOL apparently inhibited growth in both cell lines, whereas CTX showed little effect. ZOL also increased the levels of unprenylated RAS. Combined ZOL and CTX treatment was synergistic in both cell lines and was associated with inhibition of the RAS‐MAPK and AKT‐mTOR signaling pathways. Furthermore, the combination treatment was more effective in suppressing the growth of xenografts derived from both SW48 and LS174T cells; this effect was associated with increased apoptosis. These results demonstrate that ZOL inhibits the growth of colon cancer cells regardless of KRAS status, and combination therapy using ZOL and CTX enhances this growth suppression. These findings suggest a novel strategy for the treatment of CRC independent of KRAS mutational status.
publisher	John Wiley and Sons Inc.
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5057332/
_version_	1613678667332845568

Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status

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