Some of the important mutations include epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations in small cell lung cancer, human epidermal growth factor receptor (HER2) mutation in breast cancer, and BRAF mutation in melanoma.
Key examples include two monoclonal antibodies, each engaging a distinct site of human epidermal growth factor receptor 2 (HER2), in the treatment of breast cancer and a combination of antibodies to two distinct T-cell antigens for the treatment of melanoma.
Furthermore, HuRt-T<sub>EXO</sub>, but not HER2-T<sub>EXO</sub> vaccination, is capable of suppressing early stage-established HER2-expressing 4T1<sub>HER2</sub> breast cancer in its lung metastasis or subcutaneous form in BALB/c mice, and of completely protecting transgenic HLA-A2/HER2 mice from growth of HLA-A2/HER2-expressing BL6-10<sub>A2/HER2</sub> melanoma.
The examples include estrogen and progesterone receptor status determination for the use of endocrine therapy, HER2 assessment for the administration of HER2-targeting agents, EGFR and ALK gene testing for lung cancer treatment, BRAF analysis in melanoma, etc.
Notably, the ACA-28-induced apoptosis in melanoma and HER2-transformed cells was abrogated when ERK activation was blocked with a specific MEK inhibitor U0126.
We show that active Notch1 (Notch1(NIC)) and active (phosphorylated) ERBB3 and ERBB2 correlate significantly and are similarly expressed in both mutated and wild-type BRAF melanomas, suggesting these receptors are co-reactivated in melanoma to promote survival.
Mixed desmoplastic melanomas on the contrary were frequently mutated (89%), and 67% exhibited activating mutations similar to common-type cutaneous malignant melanomas (BRAF, NRAS, FGFR2, and ERBB2).
Targeting BCR-ABL in chronic myeloid leukemia (CML) or HER2 in breast cancer has led to practice-changing clinical benefits, while promising therapeutic responses have been achieved by precision medicine approaches in EGFR mutant lung cancer, colorectal cancer and BRAF mutant melanoma.
Particularly, the mutational status and/or aberrant expression of certain markers, such as EGFR, HER2, cKIT, BRAF and AR, also identified in some tumor histotypes of the salivary glands, currently represent molecular targets for new and efficacious drugs routinely employed in the treatment of other neoplasias, such as breast, lungs, GIST and melanoma.
Here we demonstrated the expression of HER2 in a wide range of human melanoma cells including a primary culture and seven cell lines, and we further investigated whether HER2 could be served as a target for T cell mediated immunotherapy of human melanoma.
These successes include imatinib for the treatment of chronic myeloid leukemia, anti-HER2 therapies (trastuzumab, pertuzumab, and lapatinib) to treat breast cancer, anti-EGFR tyrosine kinase inhibitors (gefitinib and erlotinib) to treat non-small cell lung cancer, and anti-BRAF agents (vemurafenib and dabrafenib) to treat melanoma.
Furthermore, we demonstrate that HER2-TEXO vaccine stimulates responses of CD8(+) T cells capable of not only inducing killing activity to HLA-A2(+)HER2(+) BL6-10A2/HER2melanoma and trastuzumab-resistant BT474A2 breast cancer cells in vitro but also eradicating 6-day palpable HER2(+) BT474A2 breast cancer (3-4 mm in diameter) in athymic nude mice.
In addition, antigen-specific CD4+ T cells from hybrid peptide immunized DR4-IE Tg mice synergized with HER-2/neu(435-443)-specific CD8+ T cells from HLA-A2.1 Tg HHD (H-2b) mice in producing antitumor immunity into SCID mice xenografted with the HER-2/neu+, HLA-A2.1+ and HLA-DR4+ FM3 human melanoma cell line.
We therefore examined Her2/neu expression in a very large cohort of melanoma specimens in order to determine the value of exploring trastuzumab therapy for melanoma patients.
We therefore examined Her2/neu expression in a very large cohort of melanoma specimens in order to determine the value of exploring trastuzumab therapy for melanoma patients.
c-erbB-2 overexpression does not appear to play a role in the development of primary cutaneous melanoma or in the development of metastatic melanoma, indicating that mechanisms other than c-erbB-2 overexpression are involved in the pathogenesis of cutaneous melanoma.