The non-receptor tyrosine kinase TNK2/ACK1 is a novel therapeutic target in triple negative breast cancer.

Breast cancer is the most prevalent cancer in women worldwide. About 15-20% of all breast cancers do not express estrogen receptor, progesterone receptor or HER2 receptor and hence are collectively classified as triple negative breast cancer (TNBC). These tumors are often relatively aggressive when compared to other types of breast cancer, and this issue is compounded by the lack of effective targeted therapy. In our previous phosphoproteomic profiling effort, we identified the non-receptor tyrosine kinase TNK2 as activated in a majority of aggressive TNBC cell lines. In the current study, we show that high expression of TNK2 in breast cancer cell lines correlates with high proliferation, invasion and colony forming ability. We demonstrate that knockdown of TNK2 expression can substantially suppress the invasiveness and proliferation advantage of TNBC cells in vitro and tumor formation in xenograft mouse models. Moreover, inhibition of TNK2 with small molecule inhibitor (R)-9bMS significantly compromised TNBC proliferation.Finally, we find that high levels of TNK2 expression in high-grade basal-like breast cancers correlates significantly with poorer patient outcome. Taken together, our study suggests that TNK2 is a novel potential therapeutic target for the treatment of TNBC.

Melanoma hyperpigmentation is strongly associated with KIT alterations.

KIT alterations have been identified in melanoma and treatment with imatinib has met with some success. However, the relationship between KIT and melanoma histology remains uncharacterized, and its role in melanoma pathogenesis unknown. We evaluated 70 melanomas from 70 patients seen at a single institution from 1997 to 2008. Cases were analyzed for KIT protein expression relative to histologic variables: subtype, sun damage, tumor infiltrating lymphocytes, melanoma in situ, vertical growth phase (VGP), location, and hyperpigmentation. Twenty-eight cases demonstrated 3+ membranous staining. Univariate analysis revealed 5 significant variables: sun damage (inverse, P = 0.015), tumor location (trunk>extremities>head and neck, P = 0.005), subtype (epithelioid>spindle, mixed>desmoplastic, P < 0.001), VGP (inverse, P = 0.024), and hyperpigmentation [22/26 (85% hyperpigmented cases) and 6/44 (14% nonhyperpigmented cases), P < 0.001]. Upon multivariate analysis, only hyperpigmentation and VGP remained statistically significant (P = 0.002, P = 0.019). Mutational analyses for KIT exons 9 and 11, and BRAF were performed on cases with 3+ labeling. Two of 27 of cases contained mutations in KIT exon 11, whereas only 1 case contained a V600E BRAF mutation, suggesting that KIT and BRAF mutations may be redundant events. Although KIT mutations were uncommon overall, pigmentation in conjunction with immunohistochemistry and nodular growth phase raised their frequency to 2 (40%) of 5 cases. We expand the context of KIT aberrations to involve areas other than acral and mucosal sites and demonstrate an inverse relationship between KIT abnormalities and sun damage. There is a strong correlation to hyperpigmentation that overrides factors including sun damage, tumor location, and histologic subtype, which may be used to identify cases with KIT aberrations.