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.
Lingua originale | English |
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pagine (da-a) | 108463-108479 |
Rivista | Oncotarget |
Volume | 8 |
DOI | |
Stato di pubblicazione | Pubblicato - 2017 |
Keywords
- HER3
- MAPK
- PI3K
- colon cancers
- drug resistance