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

Although the medical treatment of colorectal cancer has evolved greatly in the\r\nlast years, a significant portion of early-stage patients develops recurrence\r\nafter therapies. The current clinical trials are directed to evaluate new drug\r\ncombinations and treatment schedules. By the use of patient-derived or\r\nestablished colon cancer cell lines, we found that the tyrosine kinase receptor\r\nHER3 is involved in the mechanisms of resistance to therapies. In agreement, the \r\nimmunohistochemical analysis of total and phospho-HER3 expression in 185\r\ncolorectal cancer specimens revealed a significant correlation with lower\r\ndisease-free survival. Targeting HER3 by the use of the monoclonal antibody\r\npatritumab we found induction of growth arrest in all cell lines. Despite the\r\nhigh efficiency of patritumab in abrogating the HER3-dependent activation of PI3K\r\npathway, the HER2 and EGFR-dependent MAPK pathway is activated as a compensatory \r\nmechanism. Interestingly, we found that the MEK-inhibitor trametinib inhibits, as\r\nexpected, the MAPK pathway but induces the HER3-dependent activation of PI3K\r\npathway. The combined treatment results in the abrogation of both PI3K and MAPK\r\npathways and in a significant reduction of cell proliferation and survival. These\r\ndata suggest a new strategy of therapy for HER3-overexpressing colon cancers.