568 CK2 inhibition synergizes with MAPK inhibition to overcome resistance in acral melanoma

Abstract

Acral melanoma (AM) occurs on the palms, soles and subungual sites and occurs in a much higher proportion in darker-skinned individuals compared to cutaneous melanoma. AM is the most common subtype of melanoma in patients of African and Asian descent. AM is associated with activation mutations in the KIT gene and/or inactivating mutations in NF1 (neurofibromin1). These tumors respond poorly to currently available targeted therapies and immune checkpoint inhibition, underscoring the urgent need for treatment alternatives that improve overall survival of patients with metastatic disease. The protein kinase CK2 (casein kinase II) is upregulated in several types of cancer, including melanoma, and especially in AM. CK2 over-expression contributes to maintenance of the malignant phenotype and is associated with resistance to targeted therapies. Here, we investigated the potential of CK2 inhibition to overcome resistance to MEK inhibitors (MEKi) in preclinical models of AM. We found that in vitro treatment of NF1-null human melanoma cells with a small-molecule CK2 inhibitor (CX4945, silmitasertib) resulted in inhibition of cell proliferation. This was accompanied by downregulation of PI3K and ERK-MAPK signaling, as demonstrated by dephosphorylation of AKT (S129 and S473) and ERK (p44/42 MAPK; Thr202/Tyr204). CX4945 also showed a synergistic anti-proliferative effect with the MEKi trametinib in MTS viability assays, and an increase in apoptosis. Further, in colony formation assays, CX4945 significantly reduced the appearance of trametinib resistant colonies. To translate these findings, we treated NF1-null human melanoma cells grown as xenografts in nude mice with CX4945, and noted a significant reduction in tumor growth that resulted in stable disease. Together, our results suggest that the combination of CK2 inhibitors with MEK inhibitors, and potentially other tyrosine kinase inhibitors, may improve therapeutic outcomes in difficult to treat malignant melanomas of acral origin.