Dual targeting of HER3 and MEK may overcome HER3-dependent drug-resistance of colon cancers

Giulia Bon, Rossella Loria, Carla Azzurra Amoreo, Alessandra Verdina, Isabella Sperduti, Arianna Mastrofrancesco, Silvia Soddu, Maria Grazia Diodoro, Marcella Mottolese, Matilde Todaro, Giorgio Stassi, Michele Milella, Ruggero De Maria, Rita Falcioni

Research output: Contribution to journalArticle

Abstract

Although the medical treatment of colorectal cancer has evolved greatly in the last years, a significant portion of early-stage patients develops recurrence after therapies. The current clinical trials are directed to evaluate new drug combinations and treatment schedules. By the use of patient-derived or established colon cancer cell lines, we found that the tyrosine kinase receptor HER3 is involved in the mechanisms of resistance to therapies. In agreement, the immunohistochemical analysis of total and phospho- HER3 expression in 185 colorectal cancer specimens revealed a significant correlation with lower disease-free survival. Targeting HER3 by the use of the monoclonal antibody patritumab we found induction of growth arrest in all cell lines. Despite the high efficiency of patritumab in abrogating the HER3-dependent activation of PI3K pathway, the HER2 and EGFRdependent MAPK pathway is activated as a compensatory mechanism. Interestingly, we found that the MEK-inhibitor trametinib inhibits, as expected, the MAPK pathway but induces the HER3-dependent activation of PI3K pathway. The combined treatment results in the abrogation of both PI3K and MAPK pathways and in a significant reduction of cell proliferation and survival. These data suggest a new strategy of therapy for HER3-overexpressing colon cancers.

Original languageEnglish
Pages (from-to)108463-108479
Number of pages17
JournalOncotarget
Volume8
Issue number65
DOIs
Publication statusPublished - Jan 1 2017

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Keywords

  • Colon cancers
  • Drug resistance
  • HER3
  • MAPK
  • PI3K

ASJC Scopus subject areas

  • Oncology

Cite this

Bon, G., Loria, R., Amoreo, C. A., Verdina, A., Sperduti, I., Mastrofrancesco, A., Soddu, S., Diodoro, M. G., Mottolese, M., Todaro, M., Stassi, G., Milella, M., De Maria, R., & Falcioni, R. (2017). Dual targeting of HER3 and MEK may overcome HER3-dependent drug-resistance of colon cancers. Oncotarget, 8(65), 108463-108479. https://doi.org/10.18632/oncotarget.11400