Generalized Granuloma Annulare Associated With Dupilumab Therapy.

Atopic dermatitis is a condition characterized by xerotic and pruritic skin. While the onset of the disease is usually in childhood, it may persist into adulthood. First-line treatments include adequate moisturization, avoidance of irritants, and the application of topical corticosteroids. Dupilumab is a biologic therapy, approved for moderate-to-severe atopic dermatitis, that dampens the pruritus sensation by inhibiting the downstream effects of the T helper cell type 2 pathway by binding to the interleukin-4 receptor α subunit. The monoclonal antibody is typically well-tolerated. We present a novel case of the development of generalized granuloma annulare after treatment with dupilumab. A 71-year-old male with a history of hypertension, hyperlipidemia, chronic kidney disease, gout, and bipolar disorder presented to clinic with biopsy-proven severe atopic dermatitis. First-line treatments had been exhausted, and the patient was not an ideal candidate for traditional systemic options secondary to his poor renal function. Therapy with dupilumab was initiated and continued for two years until the patient developed biopsy-proven generalized granuloma annulare. At this time, dupilumab was discontinued and the pharmaceutical company was made aware of this side effect.

HUNK phosphorylates EGFR to regulate breast cancer metastasis.

Epidermal growth factor receptor (EGFR) is commonly over-expressed in metastatic breast cancer yet metastatic breast cancer is generally resistant to anti-EGFR therapies, and the mechanism for resistance to EGFR inhibitors in this setting is not fully understood. Hormonally up-regulated neu-associated kinase (HUNK) kinase is up-regulated in aggressive breast cancers and is thought to play a role in breast cancer metastasis. However, no studies have been conducted to examine a relationship between EGFR and HUNK in breast cancer metastasis. We performed a kinase substrate screen and identified that EGFR is phosphorylated by HUNK. Our studies show that HUNK phosphorylates EGFR at T654, enhancing receptor stability and downstream signaling. We found that increased phosphorylation of T654 EGFR correlates with increased epithelial to mesenchymal, migration and invasion, and metastasis. In addition, we found that HUNK expression correlates with overall survival and distant metastasis free survival. This study shows that HUNK directly phosphorylates EGFR at T654 to promote metastasis and is the first study to show that the phosphorylation of this site in EGFR regulates metastasis.

Co-Targeting of JNK and HUNK in Resistant HER2-Positive Breast Cancer.

Strategies for successful primary treatment of HER2-positive breast cancer include use of the HER2 inhibitors trastuzumab or lapatinib in combination with standard chemotherapy. While successful, many patients develop resistance to these HER2 inhibitors indicating an unmet need. Consequently, current research efforts are geared toward understanding mechanisms of resistance and the signaling modalities that regulate these mechanisms. We have undertaken a study to examine whether signaling molecules downstream of epidermal growth factor receptor, which often act as compensatory signaling outlets to circumvent HER2 inhibition, can be co-targeted to overcome resistance. We identified JNK signaling as a potential area of intervention and now show that inhibiting JNK using the pan-JNK inhibitor, SP600125, is effective in the HER2-positive, resistant JIMT-1 xenograft mammary tumor model. We also investigate potential combination strategies to bolster the effects of JNK inhibition and find that co-targeting of JNK and the protein kinase HUNK can prohibit tumor growth of resistant HER2-positive mammary tumors in vivo.