FOXO3a and the MAPK p38 are activated by cetuximab to induce cell death and inhibit cell proliferation and their expression predicts cetuximab efficacy in colorectal cancer

Marzi, Laetitia; Combès, Eve; Vie, Nadia; Ayrolles-Torro, Adeline; Tosi, Diego; Desigaud, Delphine; Pérez-Gracia, Esther; Larbouret, Christel; Montagut, Clara; Iglesias, Mar; Jarlier, Marta; Denis, Vincent; Linares, Laëtitia K.; Lam, Eric W.‐F.; Martineau, Pierre; Rio, Maguy Del; Gongora, Céline

doi:10.1038/bjc.2016.313

Cited by 43 publications

(35 citation statements)

References 43 publications

(62 reference statements)

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“…As a positive control, incubation with cetuximab significantly increased caspase-3 activation in spheroids compared with the other conditions ( p = 0.05), as already described [32]. …”

Section: Resultssupporting

confidence: 79%

Antibody targeting of claudin-1 as a potential colorectal cancer therapy

Cherradi

Ayrolles-Torro

Vezzo-Vié

et al. 2017

J Exp Clin Cancer Res

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BackgroundMetastatic colorectal cancer (mCRC) is one of the major causes of cancer-related death. Despite the substantial progress in mCRC management, it remains important to identify new therapeutic options and biological markers for personalized medicine. Here, we investigated the expression of claudin-1 (CLDN1), a major tight junction transmembrane protein, in the different colorectal cancer (CRC) molecular subtypes and then assessed the anti-tumor effect of a new anti-CLDN1 monoclonal antibody (mAb).MethodsGene expression profiling and immunochemistry analysis of normal and tumor tissue samples from patients with stage IV CRC were used to determine CLDN1 gene expression. Then, the 6F6 mAb against CLDN1 extracellular part was generated. Its effect on CRC cell cycle, proliferation, survival and migration was assessed in vitro, using a 3D cell culture system, flow cytometry, clonogenic and migration assays. In vivo, 6 F6 mAb efficacy was evaluated in nude mice after subcutaneous xenografts or intrasplenic injection of CRC cells.ResultsCompared with normal mucosa where it was almost exclusively cytoplasmic, in CRC samples CLDN1 was overexpressed (p < 0.001) and mainly localized at the membrane. Moreover, it was differentially expressed in the various CRC molecular subtypes. The strongest expressions were found in the consensus molecular subtype CMS2 (p < 0.001), the transit-ampliflying (p < 0.001) and the C5 subtypes (p < 0.001). Lower CLDN1 expression predicted a better outcome in the molecular subtypes C3 and C5 (p = 0.012 and p = 0.004, respectively). CLDN1 targeting with the 6 F6 mAb led to reduction of survival, growth and migration of CLDN1-positive cells. In preclinical mouse models, the 6F6 mAb decreased tumor growth and liver metastasis formation.ConclusionOur data indicate that CLDN1 targeting with an anti-CLDN1 mAb results in decreased growth and survival of CRC cells. This suggests that CLDN1 could be a new potential therapeutic target.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0558-5) contains supplementary material, which is available to authorized users.

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“…As a positive control, incubation with cetuximab significantly increased caspase-3 activation in spheroids compared with the other conditions ( p = 0.05), as already described [32]. …”

Section: Resultssupporting

confidence: 79%

Antibody targeting of claudin-1 as a potential colorectal cancer therapy

Cherradi

Ayrolles-Torro

Vezzo-Vié

et al. 2017

J Exp Clin Cancer Res

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“…13 Previous researches showed that SLC1A5 was highly expressed in many types of cancer including CRC and played an important role in promoting tumor growth. 20 However, the involvement and molecular mechanisms of SLC1A5 in cetuximab treatment on CRC remain largely unknown. 20 However, the involvement and molecular mechanisms of SLC1A5 in cetuximab treatment on CRC remain largely unknown.…”

mentioning

confidence: 99%

“…[14][15][16][17][18][19] So far, supplying glutamine for cellular energy production, macromolecular synthesis, redox homeostasis and mTOR signaling activation is the well-known mechanisms of SLC1A5 for promoting tumor growth. 20 However, the involvement and molecular mechanisms of SLC1A5 in cetuximab treatment on CRC remain largely unknown.…”

mentioning

confidence: 99%

Inhibition of SLC1A5 sensitizes colorectal cancer to cetuximab

Peng

et al. 2018

Intl Journal of Cancer

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Cetuximab resistance is a key barrier in treating metastatic colorectal cancer (mCRC). Targeting of metabolic resources import could resensitize drug-resistant cancer cells to anticancer treatments. Here we showed that the expression of the glutamine transporter solute carrier 1 family member 5 (SLC1A5) in clinical CRC samples of patients resisted to cetuximab was significantly higher than in those of patients responded to cetuximab. Inhibition of SLC1A5 by shRNA-mediated gene silencing or pharmacological inhibitor significantly suppressed the growth of CRC. Moreover, inhibition of SLC1A5 significantly enhanced the inhibitory efficacy of cetuximab on CRC proliferation both in vitro and in vivo. Mechanistically, SLC1A5 inhibition facilitated EGFR degradation through the ubiquitin-proteasome pathway, and decreased the expression of nuclear EGFR, both of which might have contribution to the improved response to cetuximab. This study provides the metabolic molecule SLC1A5 as a potential therapeutic target to increase the efficacy of cetuximab on CRC.

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“…Previous studies have evaluated the effects of cetuximab only in KRAS wild-type cell lines [14,15]. The resistance mechanism to cetuximab shown by many tumor types remains unclear, although KRAS mutation, as well as EGFR mutation and HER2 or MET activation, has been implicated [15][16][17][18][19][20][21][22]. HRAS mutation or upregulated expression of microRNA-100 and microRNA-125b have also been shown to be associated with cetuximab resistance [23,24].…”

Section: Discussionmentioning

confidence: 99%

GC1118, a novel anti-EGFR antibody, has potent KRAS mutation-independent antitumor activity compared with cetuximab in gastric cancer

Park

Jin

Hur³

et al. 2019

Gastric Cancer

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Background EGFR overexpression in gastric cancer (GC) has been reported in about 30% of patients. However, the anti-EGFR antibodies cetuximab and panitumumab have failed to improve overall survival of GC patients in combination with cytotoxic chemotherapy compared with chemotherapy alone. GC1118, a novel anti-EGFR antibody with a distinct binding epitope compared with cetuximab or panitumumab, has not been tested in GC. Methods GC cell lines, SNU-1, SNU-5, SNU-16, SNU-216, SNU-484, SNU-601, SNU-620, SNU-638, SNU-668, SNU-719, AGS, MKN-45, NCI-N87, and KATO-III, were employed to test the effect of cetuximab or GC1118 alone, and combined with the cytotoxic agent cisplatin or 5-fluorouracil (5-FU). Cells were also treat with or without high-affinity ligands EGF 20 ng/ml or HB-EGF 100 ng/ml. Results GC1118 exhibited a more potent growth inhibition effect in the majority of cell lines than cetuximab in MTT assay, regardless of the KRAS mutation status of cell lines. Co-treatment of GC1118 and cisplatin or 5-FU inhibited colony formation and migration to a greater extent, even following EGFR ligand stimulation. Ligand-induced p-AKT and p-ERK upregulation were more potently inhibited by combination treatment with GC1118 and chemotherapeutic agents compared with cetuximab plus chemotherapeutic agents. GC1118 also showed more potent anti-tumor effects compared with cetuximab in a mouse xenograft model. Conclusion Taken together, GC1118 alone or in combination with cytotoxic chemotherapeutic agents exerted more potent anti-tumor effects than cetuximab in GC cells, regardless of KRAS status. These findings support the further clinical development of GC1118 for the treatment of GC.

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FOXO3a and the MAPK p38 are activated by cetuximab to induce cell death and inhibit cell proliferation and their expression predicts cetuximab efficacy in colorectal cancer

Cited by 43 publications

References 43 publications

Antibody targeting of claudin-1 as a potential colorectal cancer therapy

Antibody targeting of claudin-1 as a potential colorectal cancer therapy

Inhibition of SLC1A5 sensitizes colorectal cancer to cetuximab

GC1118, a novel anti-EGFR antibody, has potent KRAS mutation-independent antitumor activity compared with cetuximab in gastric cancer

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