title: Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status.
abstract: 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.
authors.affiliation: Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Kato
authors.affiliation: Department of Breast and Molecular Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Futamura
authors.affiliation: Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Kanematsu
authors.affiliation: Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Siqin
authors.initials: S
authors.lastname: Gaowa
authors.affiliation: Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Mori
authors.affiliation: Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tanahashi
authors.affiliation: Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Matsuhashi
authors.affiliation: Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D004164:Diphosphonates / Q000494:pharmacology*; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D066246:ErbB Receptors; D018631:ras Proteins; D000068818:Cetuximab
keywords: cetuximab; colorectal cancer; k-ras mutant; zoledronic acid