Synergistic Antitumor Activity of Sorafenib in Combination with Epidermal Growth Factor Receptor Inhibitors in Colorectal and Lung Cancer Cells

Martinelli, Erika; Troiani, Teresa; Morgillo, Floriana; Rodolico, Gabriella; Vitagliano, Donata; Morelli, Maria Pia; Tuccillo, Concetta; Vecchione, Loredana; Capasso, Anna; Orditura, Michele; Vita, Ferdinando De; Eckhardt, S. Gail; Santoro, Massimo; Berrino, Liberato; Ciardiello, Fortunato

doi:10.1158/1078-0432.ccr-10-0923

Cited by 81 publications

(75 citation statements)

References 36 publications

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“…Specifically, this multi-TKI exhibited cytotoxic effects in different CRC cell lines regardless of their KRAS status, as described in other preclinical studies (23,24) and suggested by several phase I studies, involving a large number of patients with CRC (25)(26)(27)(28).…”

Section: Discussionsupporting

confidence: 61%

Sorafenib Overcomes Irinotecan Resistance in Colorectal Cancer by Inhibiting the ABCG2 Drug-Efflux Pump

Mazard

Causse

Simony

et al. 2013

Molecular Cancer Therapeutics

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Despite recent advances in the treatment of colorectal cancer (CRC), tumor resistance is a frequent cause of chemotherapy failure. Therefore, new treatment options are needed to improve survival of patients with irinotecan-refractory CRCs, particularly those bearing KRAS mutations that preclude the use of anti-EGFR therapies. In this study, we investigated whether sorafenib could reverse irinotecan resistance, thereby enhancing the therapeutic efficacy of routinely used irinotecan-based chemotherapy. We used both in vitro (the HCT116, SW48, SW620, and HT29 colon adenocarcinoma cell lines and four SN-38-resistant HCT-116 and SW48 clones) and in vivo models (nude mice xenografted with SN-38-resistant HCT116 cells) to test the efficacy of sorafenib alone or in combination with irinotecan or its active metabolite, SN-38. We have shown that sorafenib improved the antitumoral activity of irinotecan in vitro, in both parental and SN-38-resistant colon adenocarcinoma cell lines independently of their KRAS status, as well as in vivo, in xenografted mice. By inhibiting the drug-efflux pump ABCG2, sorafenib favors irinotecan intracellular accumulation and enhances its toxicity. Moreover, we found that sorafenib improved the efficacy of irinotecan by inhibiting the irinotecanmediated p38 and ERK activation. In conclusion, our results show that sorafenib can suppress resistance to irinotecan and suggest that sorafenib could be used to overcome resistance to irinotecan-based chemotherapies in CRC, particularly in KRAS-mutated tumors.

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Section: Discussionsupporting

confidence: 61%

Sorafenib Overcomes Irinotecan Resistance in Colorectal Cancer by Inhibiting the ABCG2 Drug-Efflux Pump

Mazard

Causse

Simony

et al. 2013

Molecular Cancer Therapeutics

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“…GEO and SW48 cells are differentiated colon carcinoma cells with little or no ability to migrate or to invade in vitro (35). GEO-CR and SW48-CR cells acquired the ability to migrate in an in vitro migration assay ( Fig.…”

Section: Treatment With a Selective Met Tki Sensitizes Geo-cr And Sw4mentioning

confidence: 99%

Increased TGF-α as a Mechanism of Acquired Resistance to the Anti-EGFR Inhibitor Cetuximab through EGFR–MET Interaction and Activation of MET Signaling in Colon Cancer Cells

Troiani

Martinelli

Napolitano

et al. 2013

Clinical Cancer Research

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134

145

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Purpose: Although cetuximab, an anti-EGF receptor (EGFR) monoclonal antibody, is an effective treatment for patients with KRAS wild-type metastatic colorectal cancer (mCRC), its clinical use is limited by onset of resistance.Experimental Design: We characterized two colorectal cancer models to study the mechanisms of acquired resistance to cetuximab.Results: Following chronic treatment of nude mice bearing cetuximab-sensitive human GEO colon xenografts, cetuximab-resistant GEO (GEO-CR) cells were obtained. In GEO-CR cells, proliferation and survival signals were constitutively active despite EGFR inhibition by cetuximab treatment. Whole gene expression profiling identified a series of genes involved in the hepatocyte growth factor (HGF)-MET-dependent pathways, whichwere upregulated in GEO-CR cells.Furthermore,activated, phosphorylated MET was detected in GEO-CR cells. A second colorectal cancer cell line with acquired resistance to cetuximab was obtained (SW48-CR). Inhibition of MET expression by siRNA restored cetuximab sensitivity in GEO-CR and SW48-CR cells, whereas exogenousactivation ofMETbyHGFstimulationin cetuximab-sensitiveGEOandSW48cells inducedresistance to cetuximab. Treatment of GEO-CR and SW48-CR cells with PHA665752, a selective MET inhibitor, inhibited cell growth, proliferation, and survival signals and impaired cancer cell migration. Overexpression of TGF-a, a specific EGFR ligand, was involved in the acquisition of cetuximab resistance in GEO-CR and SW48-CR cells. In fact, TGF-a overexpression induced the EGFR-MET interaction, with subsequent MET phosphorylation and activation of MET downstream effectors in GEO-CR and SW48-CR cells.Conclusions: These results suggest that overexpression of TGF-a through induction of EGFR-MET interaction contributes to cetuximab resistance in colorectal cancer cells. The combined inhibition of EGFR and MET receptor could represent a strategy for preventing and/or overcoming cetuximab resistance in patients with colorectal cancer.

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“…Cross-talk between the EGFR-dependent autocrine pathway and of VEGFR-dependent signaling in cancer cells has been shown by the study of Martinelli et al (2010). Moreover, they evaluated the in vitro and in vivo antitumor activity of anti-EGFR drugs, such as erlotinib, cetuximab and sorafenib.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, they evaluated the in vitro and in vivo antitumor activity of anti-EGFR drugs, such as erlotinib, cetuximab and sorafenib. Martinelli et al (2010) displayed the anti-proliferative effects of sorafenib on non-small cell lung cancer and colorectal cells (Martinelli et al, 2010). Simonelli et al (2013) used sorafenib and lapatinib combination in 30 patients with refractory solid tumors and reported that combination of sorafenib and lapatinib achieved in stabilization of disease.…”

Section: Discussionmentioning

confidence: 99%

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Investigation of Antitumor Effects of Sorafenib and Lapatinib Alone and in Combination on MCF-7 Breast Cancer Cells

Kaçan¹,

Altun²,

Altun³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Synergistic Antitumor Activity of Sorafenib in Combination with Epidermal Growth Factor Receptor Inhibitors in Colorectal and Lung Cancer Cells

Cited by 81 publications

References 36 publications

Sorafenib Overcomes Irinotecan Resistance in Colorectal Cancer by Inhibiting the ABCG2 Drug-Efflux Pump

Sorafenib Overcomes Irinotecan Resistance in Colorectal Cancer by Inhibiting the ABCG2 Drug-Efflux Pump

Increased TGF-α as a Mechanism of Acquired Resistance to the Anti-EGFR Inhibitor Cetuximab through EGFR–MET Interaction and Activation of MET Signaling in Colon Cancer Cells

Investigation of Antitumor Effects of Sorafenib and Lapatinib Alone and in Combination on MCF-7 Breast Cancer Cells

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