Maintenance treatment with cetuximab and BAY86-9766 increases antitumor efficacy of irinotecan plus cetuximab in human colorectal cancer xenograft models

Teresa Troiani, Stefania Napolitano, Giulia Martini, Erika Martinelli, Claudia Cardone, Nicola Normanno, Donata Vitagliano, Floriana Morgillo, Francesca Fenizia, Matilde Lambiase, Luigi Formisano, Roberto Bianco, Davide Ciardiello, Fortunato Ciardiello

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Abstract

Purpose: The use of cetuximab in the treatment of metastatic colorectal cancer is limited by development of resistance. Experimental Design: We have investigated in three models of highly epidermal growth factor receptor (EGFR)-dependent colorectal cancer xenografts, the effect of maintenance therapy with different kinase inhibitors alone or in combination with cetuximab, after cytotoxic treatment induction with irinotecan plus cetuximab. Results: SW48, LIM 1215, and GEO colorectal cancer cell lines were engrafted into nude mice and treated for 3 weeks with irinotecan and/or cetuximab. The combined treatment induced a significant reduction of tumor size. A subsequent experiment was performed in all three xenograft models in which after an induction treatment with irinotecan plus cetuximab, mice were randomly assigned to one of the following treatments: control, cetuximab, regorafenib, a selective PIK3CA inhibitor (PIK3CAi), a selective MEK inhibitor (MEKi), and /or the combination of each inhibitor with cetuximab. The cetuximab plus MEKi treatment determined the best antitumor activity with suppression of tumor growth. This effect was prolonged for 13 to 15 weeks after cessation of therapy and was accompanied by prolonged survival. Antitumor activity was accompanied by inhibition of the MAPK and MEK pathways. Moreover, in the cetuximab plus MEKi-treated SW48 xenograft group, KRAS mutations as a mechanism of acquired resistance were detected in 25% of cases compared with 75% KRAS mutations in the MEKi-treated group. Conclusions: A possible strategy to prevent and/or overcome resistance to anti-EGFR inhibitors in metastatic colorectal cancer is a maintenance therapy with cetuximab plus MEKi after an initial treatment with irinotecan plus cetuximab.

Original languageEnglish
Pages (from-to)4153-4164
Number of pages12
JournalClinical Cancer Research
Volume21
Issue number18
DOIs
Publication statusPublished - Sep 15 2015

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irinotecan
Heterografts
Colorectal Neoplasms
Mitogen-Activated Protein Kinase Kinases
Epidermal Growth Factor Receptor
Cetuximab

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Maintenance treatment with cetuximab and BAY86-9766 increases antitumor efficacy of irinotecan plus cetuximab in human colorectal cancer xenograft models. / Troiani, Teresa; Napolitano, Stefania; Martini, Giulia; Martinelli, Erika; Cardone, Claudia; Normanno, Nicola; Vitagliano, Donata; Morgillo, Floriana; Fenizia, Francesca; Lambiase, Matilde; Formisano, Luigi; Bianco, Roberto; Ciardiello, Davide; Ciardiello, Fortunato.

In: Clinical Cancer Research, Vol. 21, No. 18, 15.09.2015, p. 4153-4164.

Research output: Contribution to journalArticle

Troiani, T, Napolitano, S, Martini, G, Martinelli, E, Cardone, C, Normanno, N, Vitagliano, D, Morgillo, F, Fenizia, F, Lambiase, M, Formisano, L, Bianco, R, Ciardiello, D & Ciardiello, F 2015, 'Maintenance treatment with cetuximab and BAY86-9766 increases antitumor efficacy of irinotecan plus cetuximab in human colorectal cancer xenograft models', Clinical Cancer Research, vol. 21, no. 18, pp. 4153-4164. https://doi.org/10.1158/1078-0432.CCR-15-0211
Troiani, Teresa ; Napolitano, Stefania ; Martini, Giulia ; Martinelli, Erika ; Cardone, Claudia ; Normanno, Nicola ; Vitagliano, Donata ; Morgillo, Floriana ; Fenizia, Francesca ; Lambiase, Matilde ; Formisano, Luigi ; Bianco, Roberto ; Ciardiello, Davide ; Ciardiello, Fortunato. / Maintenance treatment with cetuximab and BAY86-9766 increases antitumor efficacy of irinotecan plus cetuximab in human colorectal cancer xenograft models. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 18. pp. 4153-4164.
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abstract = "Purpose: The use of cetuximab in the treatment of metastatic colorectal cancer is limited by development of resistance. Experimental Design: We have investigated in three models of highly epidermal growth factor receptor (EGFR)-dependent colorectal cancer xenografts, the effect of maintenance therapy with different kinase inhibitors alone or in combination with cetuximab, after cytotoxic treatment induction with irinotecan plus cetuximab. Results: SW48, LIM 1215, and GEO colorectal cancer cell lines were engrafted into nude mice and treated for 3 weeks with irinotecan and/or cetuximab. The combined treatment induced a significant reduction of tumor size. A subsequent experiment was performed in all three xenograft models in which after an induction treatment with irinotecan plus cetuximab, mice were randomly assigned to one of the following treatments: control, cetuximab, regorafenib, a selective PIK3CA inhibitor (PIK3CAi), a selective MEK inhibitor (MEKi), and /or the combination of each inhibitor with cetuximab. The cetuximab plus MEKi treatment determined the best antitumor activity with suppression of tumor growth. This effect was prolonged for 13 to 15 weeks after cessation of therapy and was accompanied by prolonged survival. Antitumor activity was accompanied by inhibition of the MAPK and MEK pathways. Moreover, in the cetuximab plus MEKi-treated SW48 xenograft group, KRAS mutations as a mechanism of acquired resistance were detected in 25{\%} of cases compared with 75{\%} KRAS mutations in the MEKi-treated group. Conclusions: A possible strategy to prevent and/or overcome resistance to anti-EGFR inhibitors in metastatic colorectal cancer is a maintenance therapy with cetuximab plus MEKi after an initial treatment with irinotecan plus cetuximab.",
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T1 - Maintenance treatment with cetuximab and BAY86-9766 increases antitumor efficacy of irinotecan plus cetuximab in human colorectal cancer xenograft models

AU - Troiani, Teresa

AU - Napolitano, Stefania

AU - Martini, Giulia

AU - Martinelli, Erika

AU - Cardone, Claudia

AU - Normanno, Nicola

AU - Vitagliano, Donata

AU - Morgillo, Floriana

AU - Fenizia, Francesca

AU - Lambiase, Matilde

AU - Formisano, Luigi

AU - Bianco, Roberto

AU - Ciardiello, Davide

AU - Ciardiello, Fortunato

PY - 2015/9/15

Y1 - 2015/9/15

N2 - Purpose: The use of cetuximab in the treatment of metastatic colorectal cancer is limited by development of resistance. Experimental Design: We have investigated in three models of highly epidermal growth factor receptor (EGFR)-dependent colorectal cancer xenografts, the effect of maintenance therapy with different kinase inhibitors alone or in combination with cetuximab, after cytotoxic treatment induction with irinotecan plus cetuximab. Results: SW48, LIM 1215, and GEO colorectal cancer cell lines were engrafted into nude mice and treated for 3 weeks with irinotecan and/or cetuximab. The combined treatment induced a significant reduction of tumor size. A subsequent experiment was performed in all three xenograft models in which after an induction treatment with irinotecan plus cetuximab, mice were randomly assigned to one of the following treatments: control, cetuximab, regorafenib, a selective PIK3CA inhibitor (PIK3CAi), a selective MEK inhibitor (MEKi), and /or the combination of each inhibitor with cetuximab. The cetuximab plus MEKi treatment determined the best antitumor activity with suppression of tumor growth. This effect was prolonged for 13 to 15 weeks after cessation of therapy and was accompanied by prolonged survival. Antitumor activity was accompanied by inhibition of the MAPK and MEK pathways. Moreover, in the cetuximab plus MEKi-treated SW48 xenograft group, KRAS mutations as a mechanism of acquired resistance were detected in 25% of cases compared with 75% KRAS mutations in the MEKi-treated group. Conclusions: A possible strategy to prevent and/or overcome resistance to anti-EGFR inhibitors in metastatic colorectal cancer is a maintenance therapy with cetuximab plus MEKi after an initial treatment with irinotecan plus cetuximab.

AB - Purpose: The use of cetuximab in the treatment of metastatic colorectal cancer is limited by development of resistance. Experimental Design: We have investigated in three models of highly epidermal growth factor receptor (EGFR)-dependent colorectal cancer xenografts, the effect of maintenance therapy with different kinase inhibitors alone or in combination with cetuximab, after cytotoxic treatment induction with irinotecan plus cetuximab. Results: SW48, LIM 1215, and GEO colorectal cancer cell lines were engrafted into nude mice and treated for 3 weeks with irinotecan and/or cetuximab. The combined treatment induced a significant reduction of tumor size. A subsequent experiment was performed in all three xenograft models in which after an induction treatment with irinotecan plus cetuximab, mice were randomly assigned to one of the following treatments: control, cetuximab, regorafenib, a selective PIK3CA inhibitor (PIK3CAi), a selective MEK inhibitor (MEKi), and /or the combination of each inhibitor with cetuximab. The cetuximab plus MEKi treatment determined the best antitumor activity with suppression of tumor growth. This effect was prolonged for 13 to 15 weeks after cessation of therapy and was accompanied by prolonged survival. Antitumor activity was accompanied by inhibition of the MAPK and MEK pathways. Moreover, in the cetuximab plus MEKi-treated SW48 xenograft group, KRAS mutations as a mechanism of acquired resistance were detected in 25% of cases compared with 75% KRAS mutations in the MEKi-treated group. Conclusions: A possible strategy to prevent and/or overcome resistance to anti-EGFR inhibitors in metastatic colorectal cancer is a maintenance therapy with cetuximab plus MEKi after an initial treatment with irinotecan plus cetuximab.

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