Oncotarget

Research Papers:

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 and Rita Falcioni _

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Oncotarget. 2017; 8:108463-108479. https://doi.org/10.18632/oncotarget.11400

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Abstract

Giulia Bon1,*, Rossella Loria1,*, Carla Azzurra Amoreo1, Alessandra Verdina1, Isabella Sperduti1, Arianna Mastrofrancesco2, Silvia Soddu1, Maria Grazia Diodoro1, Marcella Mottolese1, Matilde Todaro3, Giorgio Stassi3, Michele Milella4, Ruggero De Maria5 and Rita Falcioni1

1Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy

2Physiopathology Laboratory of Skin, IRCCS San Gallicano Dermatological Institute, Rome, Italy

3Surgical and Oncological Sciences, University of Palermo, Palermo, Italy

4Department of Experimental Clinical Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy

5General Pathology, Catholic University of Rome, Rome, Italy

*These authors contributed equally to this work

Correspondence to:

Rita Falcioni, email: [email protected]

Ruggero De Maria, email: [email protected]

Keywords: colon cancers, HER3, PI3K, MAPK, drug resistance

Received: April 21, 2016     Accepted: July 10, 2016     Published: August 19, 2016

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 EGFR-dependent 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.


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